Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation

ABSTRACT

Provided are substituted heteroaryl aldehydes and derivatives thereof that act as allosteric modulators of hemoglobin, methods and intermediates for their preparation, pharmaceutical compositions comprising the modulators, and methods for their use in treating disorders mediate by hemoglobin and disorders that would benefit from increased tissue oxygenation.

REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No. 15/391,669, filed Dec. 27, 2016, which is a continuation of U.S. patent application Ser. No. 14/662,145, filed Mar. 18, 2015, which is a continuation of U.S. patent application Ser. No. 13/730,730, filed Dec. 28, 2012, now U.S. Pat. No. 9,012,450, which claims benefit under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application Nos. 61/661,327, filed Jun. 18, 2012, and 61/581,063 ,filed Dec. 28, 2011, the disclosures of each of which are hereby incorporated by reference in their entireties for all purposes.

FIELD OF THE INVENTION

The present invention generally relates to substituted heteroaryl aldehydes and derivatives thereof that act as allosteric modulators of hemoglobin, methods and intermediates for their preparation, pharmaceutical compositions comprising the modulators, and methods for their use in treating disorders mediate by hemoglobin and disorders that would benefit from increased tissue oxygenation.

BACKGROUND OF THE INVENTION

Hemoglobin (Hb) is a tetrameric protein in red blood cells that transports up to four oxygen molecules from the lungs to various tissues and organs throughout the body. Hemoglobin binds and releases oxygen through conformational changes, and is in the tense (T) state when it is unbound to oxygen and in the relaxed (R) state when it is bound to oxygen. The equilibrium between the two conformational states is under allosteric regulation. Natural compounds such as 2,3-bisphosphoglycerate (2,3-BPG), protons, and carbon dioxide stabilize hemoglobin in its de-oxygenated T state, while oxygen stabilizes hemoglobin in its oxygenated R state. Other relaxed R states have also been found, however their role in allosteric regulation has not been fully elucidated.

Sickle cell disease is a prevalent disease particularly among those of African and Mediterranean descent. Sickle hemoglobin (HbS) contains a point mutation where glutamic acid is replaced with valine, allowing the T state to become susceptible to polymerization to give the HbS containing red blood cells their characteristic sickle shape. The sickled cells are also more rigid than normal red blood cells, and their lack of flexibility can lead to blockage of blood vessels. Certain synthetic aldehydes have been found to shift the equilibrium from the polymer forming T state to the non-polymer forming R state (Nnamani et al. Chemistry & Biodiversity Vol. 5, 2008 pp. 1762-1769) by acting as allosteric modulators to stabilize the R state through formation of a Schiff base with an amino group on hemoglobin.

U.S. Pat. No. 7,160,910 discloses 2-furfuraldehydes and related compounds that are also allosteric modulators of hemoglobin. One particular compound 5-hydroxymethyl-2-furfuraldehyde (5HMF) was found to be a potent hemoglobin modulator both in vitro and in vivo. Transgenic mice producing human HbS that were treated with 5HMF were found to have significantly improved survival times when exposed to extreme hypoxia (5% oxygen). Under these hypoxic conditions, the 5HMF treated mice were also found to have reduced amounts of hypoxia-induced sickled red blood cells as compared to the non-treated mice.

A need exists for therapeutics that can shift the equilibrium between the deoxygenated and oxygenated states of Hb to treat disorders that are mediated by Hb or by abnormal Hb such as HbS. A need also exists for therapeutics to treat disorders that would benefit from having Hb in the R state with an increased affinity for oxygen. Such therapeutics would have applications ranging, for example, from sensitizing hypoxic tumor cells that are resistant to standard radiotherapy or chemotherapy due to the low levels of oxygen in the cell, to treating pulmonary and hypertensive disorders, and to promoting wound healing.

BRIEF SUMMARY OF THE INVENTION

The present invention provides, in one aspect, allosteric modulators of hemoglobin. In another aspect, provided are pharmaceutical compositions comprising the allosteric modulators disclosed herein. In other aspects, provided are methods for treating disorders mediated by hemoglobin and methods for increasing tissue oxygenation for treating disorders that would benefit from increased oxygenation, such methods comprising administering the allosteric modulators disclosed herein to a subject in need thereof. In still other aspects, provided are methods for preparing the allosteric modulators disclosed herein. These and other embodiments of the invention are more fully described in the description that follows.

DETAILED DESCRIPTION OF THE INVENTION

I. Definitions

As used herein, the below terms have the following meanings unless specified otherwise.

The abbreviations used herein are conventional, unless otherwise defined: aq=aqueous; Boc=t-butylcarboxy, (Boc)₂O=di-tert-butyl dicarbonate, ° C.=degrees celcius, mCPBA=m-chloroperoxybenzoic acid, DCM=dichloromethane (CH₂Cl₂), DIBAL=diisobutylaluminum hydride, DIEA=diisopropylethyl amine; DMF=dimethyl formamide, EtOAc=ethyl acetate, EtOH=ethanol, g=gram, H₂=hydrogen; H₂O=water; HBr=hydrogen bromide; HCl=hydrogen chloride, HPLC=high pressure liquid chromatography, h=hour, LAH=lithium aluminum hydride (LiAlH₄); MeCN=acetonitrile; LRMS=Low Resolution Mass Spectrum MS=Mass Spectrum, m/z=mass to charge ratio, MHz=Mega Hertz, MeOH=methanol, μM=micromolar, μL=microliter, mg=milligram, mM=millimolar, mmol=millimole, mL=milliliter, min=minute, M=molar, Na₂CO₃=sodium carbonate, ng=nanogram, N=Normal, NMR=nuclear magnetic resonance, Pd/C=palladium on carbon, rp=reverse phase, sat=saturated, rt=room temperature, SEM=(2-(trimethylsilyl)ethoxy)methyl, TEA=triethylamine, THF=tetrahydrofuran, TFA=trifluoroacetic acid, TLC=thin layer chromatography, and TMS=trimethylsilyl.

It is noted here that as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise.

“Alkoxy” refers to —O(alkyl) where alkyl as defined herein. Representative examples of alkoxy groups include methoxy, ethoxy, t-butoxy, and the like.

“Alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, fully saturated aliphatic hydrocarbon radical having the number of carbon atoms designated. For example, “C₁₋₈alkyl” refers to a hydrocarbon radical straight or branched, containing from 1 to 8 carbon atoms that is derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Alkyl includes branched chain isomers of straight chain alkyl groups such as isopropyl, t-butyl, isobutyl, sec-butyl, and the like. Representative alkyl groups include straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. Further representative alkyl groups include straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.

“Alkenyl” refers to a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical having the number of carbon atoms indicated in the prefix and containing at least one double bond, but no more than three double bonds. For example, C₂₋₈alkenyl is meant to include, ethenyl, propenyl, 1,3-butadienyl and the like.

“Alkynyl” means a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond and having the number of carbon atoms indicated in the prefix. The term “alkynyl” is also meant to include those alkyl groups having one triple bond and one double bond. For example, C₂₋₈alkynyl is meant to include ethynyl, propynyl and the like.

The term “allosteric modulators” refers to compounds that bind to hemoglobin to modulate its affinity for oxygen. In one group of embodiments, the allosteric modulators act to stabilize or destabilize a particular hemoglobin conformation. In one group of embodiments, the modulators stabilize the relaxed R state. In other embodiments, the modulators destabilize the tense T state. In one group of embodiments, the allosteric modulators can destabilize one conformation while stabilizing another. In some such embodiments, the modulators stabilize a relaxed R state and destabilize the tense T state. The modulators, in addition to modulating the affinity of hemoglobin for oxygen, may also confer additional properties to hemoglobin such as increasing its solubility. The present disclosure is not intended to be limited to the mechanism by which the allosteric modulators interact with and regulate hemoglobin. In one group of embodiments, the allosteric modulators inhibit the polymerization of HbS and the sickling of red blood cells. In one group of embodiments, the binding of the allosteric modulators provided herein to hemoglobin can occur through covalent or non-covalent interactions. In one embodiment, the allosteric modulators react through its aldehyde substituent with an amine group on a hemoglobin amino acid side chain to form a Schiffbase.

“Amino” refers to a monovalent radical —NH₂.

“Aryl” by itself or as part of another substituent refers to a polyunsaturated, aromatic, hydrocarbon group containing from 6 to 14 carbon atoms, which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently. Thus the phrase includes, but is not limited to, groups such as phenyl, biphenyl, anthracenyl, naphthyl by way of example. Non-limiting examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl and 4-biphenyl.

“Bond” when used as an element in a Markush group means that the corresponding group does not exist, and the groups of both sides are directly linked.

“Cycloalkyl” refers to a saturated or partially saturated cyclic group of from 3 to 14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings including fused, bridged, and spiro ring systems. The term “cycloalkyl” includes cycloalkenyl groups, a partially saturated cycloalkyl ring having at least one site of >C═C< ring unsaturation. Examples of cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and cyclohexenyl. “C_(u′-v′)cycloalkyl” refers to cycloalkyl groups having u′ to v′ carbon atoms as ring members. “C_(u′-v′)cycloalkenyl” refers to cycloalkenyl groups having u′ to v′ carbon atoms as ring members.

The term “hemoglobin” as used herein refers to any hemoglobin protein, including normal hemoglobin (Hb) and sickle hemoglobin (HbS).

“Heteroaryl” refers to a cyclic or polycyclic radical having at least one aromatic ring and from one to five ring heteroatom selected from N, O, and S, and optionally one or more oxo (═O) substituents attached to one or more carbon ring atoms, and wherein the nitrogen and sulfur ring atoms are optionally oxidized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom or through a carbon atom and can contain 5 to 10 carbon atoms. Heteroaryl groups include polycyclic aromatic ring(s) fused to non-aromatic cycloalkyl or heterocycloalkyl groups, and where the point of attachment to the remainder of the molecule can be through any suitable ring atom of any ring. In a polycyclic heteroaryl group, the ring heteroatom(s) can be in either an aromatic or non-aromatic ring or both. The term “aromatic ring” include any ring having at least one planar resonance structure where 2n+2 pi electrons are delocalized about the ring. Examples of heteroaryl groups include, but are not limited to, imidazopyridinyl groups, pyrrolopyridinyl groups, pyrazolopyridinyl groups, triazolopyridinyl groups, pyrazolopyrazinyl groups, pyridinyl groups, pyrazinyl groups, oxazolyl groups, imidazolyl groups, triazolyl groups, tetrazolyl groups, pyrazolyl groups, quinolinyl groups, isoquinolinyl groups, indazolyl groups, benzooxazolyl groups, naphthyridinyl groups, and quinoxalinyl groups. Other non-limiting examples of heteroaryl groups include xanthine, hypoxanthine, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, benzopyrazolyl, 5-indolyl, azaindole, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, 6-quinolyl 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl and 4-pyrimidyl. “Bicyclic heteroaryl” refers to a heteroaryl radical that contains two rings.

The term “heterocycloalkyl” refers to a cycloalkyl group containing at least one ring heteroatom and optionally one or more oxo substituents. As used herein, the term “heteroatom” is meant to include oxygen (O), nitrogen (N), and sulfur (S), wherein the heteroatoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Each heterocycle can be attached at any available ring carbon or heteroatom. Each heterocycle may have one or more rings. When multiple rings are present, they can be fused together. Each heterocycle typically contains 1, 2, 3, 4 or 5, independently selected heteroatoms. Preferably, these groups contain 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, 0, 1, 2, 3, 4 or 5 nitrogen atoms, 0, 1 or 2 sulfur atoms and 0, 1 or 2 oxygen atoms. More preferably, these groups contain 1, 2 or 3 nitrogen atoms, 0-1 sulfur atoms and 0-1 oxygen atoms. Non-limiting examples of heterocycle groups include morpholin-3-one, piperazine-2-one, piperazin-1-oxide, piperidine, morpholine, piperazine, isoxazoline, pyrazoline, imidazoline, pyrrolidine, and the like.

“Halo” or “halogen” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl”, are meant to include alkyl in which one or more hydrogen is substituted with halogen atoms which can be the same or different, in a number ranging from one up to the maximum number of halogens permitted e.g. for alkyl, (2m′+1), where m′ is the total number of carbon atoms in the alkyl group. For example, the term “haloC₁₋₈alkyl” is meant to include difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. The term “haloalkenyl”, and “haloalkynyl” refers to alkenyl and alkynyl radicals having one or more halogen atoms. Additionally, term “haloalkoxy” refers to an alkoxy radical substituted with one or more halogen atoms. In one group of embodiments, the haloakyl, haloalkenyl, haloalkynyl, and haloalkoxy groups have from one to 5 or from one to 3 halo atoms. Examples of haloalkoxy groups include difluoromethoxy and trifluoromethoxy. In one group of embodiments, the halo atoms of the haloalkenyl and haloalkynyl groups are attached to the aliphatic portions of these groups.

The terms “optional” or “optionally” as used throughout the specification means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “heteroaryl group optionally substituted with an alkyl group means that the alkyl may but need not be present, and the description includes situations where the heteroaryl group is substituted with an alkyl group and situations where the heteroaryl group is not substituted with the alkyl group.

“Oxo” refers to the divalent atom ═O.

In each of the above embodiments designating a number of atoms e.g. “C₁₋₈” is meant to include all possible embodiments that have one fewer atom. Non-limiting examples include C₁₋₄, C₁₋₅, C₁₋₆, C₁₋₇, C₂₋₈, C₂₋₇, C₃₋₈, C₃₋₇ and the like.

The term “pharmaceutically acceptable salts” is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethanine and the like. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge, S. M. et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1-19, 1977). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.

The term “pharmaceutically acceptable carrier or excipient” means a carrier or excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable carrier or excipient” as used in the specification and claims includes both one and more than one such carrier or excipient.

The terms “pharmaceutically effective amount”, “therapeutically effective amount” or “therapeutically effective dose” refers to the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. The term “therapeutically effective amount” includes that amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated. The therapeutically effective amount will vary depending on the compound, the disorder or condition and its severity and the age, weight, etc., of the mammal to be treated.

“Protecting group” refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3^(rd) Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl (“TES”), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl (“NVOC”) and the like. Representative hydroxy protecting groups include, but are not limited to, those where the hydroxy group is either acylated or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPPS groups) and allyl ethers.

The term “aldehyde protecting group” refers to any known protecting group used to mask the aldehyde functionality. Aldehyde protecting groups include acetals and hemiacetals. The acetals and hemiacetals can be prepared from C₁₋₈ alcohols or C₂₋₈ diols. In one group of embodiments, the aldehyde protecting group is a five or six membered cyclic acetal formed from condensation of the aldehyde with ethylene or propylene glycol. In another group of embodiments the aldehyde protecting group is an imine or hydroxyimine. The aldehyde protecting groups of the present disclosure also include prodrug groups that convert the aldehyde to a prodrug, where the aldehyde is formed in vivo as the active agent under physiological conditions upon administration of the prodrug. The prodrug group can also serve to increase the bioavailability of the aldehyde. In one group of embodiments, the prodrug group is hydrolyzed in vivo to the aldehyde. In one group of embodiments, the aldehyde protecting group is a thiazolidine or N-acetylthiazolidine prodrug group. In one group of embodiments, the aldehyde protecting group is a thiazolidine prodrug group disclosed in U.S. Pat. No. 6,355,661. In one group of embodiments the modulators provided herein are condensed with L-cysteine or a L-cysteine derivative to form the corresponding thiazolidine protected aldehyde prodrug. In one group of embodiments, the thiazolidine has the formula

wherein R¹¹ is selected from the group consisting of OH, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, N(R¹³)₂ where R¹³ is independently H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R¹² is H or -L-R¹⁴, where L is carbonyl or sulfonyl; R¹⁴ is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; the wavy line signifies the point of attachment to the phenyl ring of the allosteric modulators disclosed herein; and the term “substituted” refers to substitution by one or more substituents selected from the group consisting of COOH, CHO, oxyacyl, acyloxy, cycloacyloxy, phenol, phenoxy, pyridinyl, pyrrolidinyl, amino, amido, hydroxy, alkoxy, cycloalkoxy, F, Cl, Br, NO₂, cyano, sulfuryl, and the like. In one group of embodiments, provided are modulators having a thiazolidine protecting group where R¹¹ is alkoxy and R¹² is H, or where R¹¹ is OH and R¹² is —C(O)alkyl, or where R¹¹ is NH(heteroaryl) and R¹² is —C(O)alkyl.

The term “sickle cell disease” refers to diseases mediated by sickle hemoglobin (HbS) that results from a single point mutation in the hemoglobin (Hb). Sickle cell diseases includes sickle cell anemia, sickle-hemoglobin C disease (HbSC), sickle beta-plus-thalassaemia (HbS/β⁺) and sickle beta-zero-thalassaemia (HbS/β⁰).

The “subject” is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is a human.

“Tautomer” refers to alternate forms of a molecule that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a —N═C(H)—NH— ring atom arrangement, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles. A person of ordinary skill in the art would recognize that other tautomeric ring atom arrangements are possible.

The terms “treat”, “treating”, “treatment” and grammatical variations thereof as used herein, includes partially or completely delaying, alleviating, mitigating or reducing the intensity, progression, or worsening of one or more attendant symptoms of a disorder or condition and/or alleviating, mitigating or impeding one or more causes of a disorder or condition. Treatments according to the invention may be applied preventively, prophylactically, pallatively or remedially.

The symbol > when used in connection with a substituent signifies that the substituent is a divalent substituent attached to two different atoms through a single atom on the substituent.

The term “wavy line” signifies the point of attachment of the substituent to the remainder of the molecule. When the wavy line is not depicted as being specifically appended to a specific ring atom, the point of attachment can be to any suitable atom of the substituent. For example, the wavy line in the following structure:

is intended to include, as the point of attachment, any of the six substitutable carbon atoms.

Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. “Stereoisomer” and “stereoisomers” refer to compounds that exist in different stereoisomeric forms if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual stereoisomers or as mixtures. Stereoisomers include enantiomers and diastereomers. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (−)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of ADVANCED ORGANIC CHEMISTRY, 4th edition J. March, John Wiley and Sons, New York, 1992) differ in the chirality of one or more stereocenters.

The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with isotopes, such as for example deuterium (²H), tritium (³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent “alkoxyalkyl” refers to an akyl group that is substituted with alkoxy and “hydoxyalkyl” refers to an akyl group that is substituted with hydroxy. For both of these substituents, the point of attachment is at the alkyl group.

It is understood that the definitions and formulas provided herein are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups). Such impermissible substitution patterns are well known to the skilled artisan.

II. Hemoglobin Modulators

In one group of embodiments, provided is a compound of Formula (I):

or a tautomer or pharmaceutically acceptable salt thereof,

wherein Q is selected from the group consisting of aryl, heteroaryl, and heterocycloalkyl, each optionally substituted with one to three R^(a);

Y is O or CR^(1a)R^(1b), where R^(1a) is H or halo and R^(1b) is selected from the group consisting of H, halo, and OH;

X is selected from the group consisting of O, >CH(CH₂)_(n)R⁸, and C(R⁹)₂ where n is 0 or 1, R⁸ is OH, and R⁹ is independently H or halo; or Y—X taken together is —NHC(O)— or —C(O)NH—;

R², R³, R⁴, and R⁵ are independently absent or selected from the group consisting of hydrogen, halo, R^(b), OR^(d), O(CH₂)_(z)OR^(d), O(CH₂)_(z)NR^(d)R^(d), OC(O)R^(c), SR^(d), CN, NO₂, CO₂R^(d), CONR^(d)R^(d), C(O)R^(d), OC(O)NR^(d)R^(d), NR^(d)R^(d), NR^(d)C(O)R^(e), NR^(d)C(O)₂R^(e), NR^(d)C(O)NR^(d)R^(d), S(O)R^(c), S(O)₂R^(c), NR^(d)S(O)₂R^(c), S(O)₂NR^(d)R^(d), and N₃ where z is 0, 1, 2, or 3; or R⁵ is —(CH₂)_(p)R^(5a) where p is 0 or 1 and R^(5a) is OH;

R⁶ and R⁷ together form oxo or an aldehyde protecting group, or R⁶ together with R^(1b), R⁸, or R⁵ forms a cyclic ether where one of R^(1b), R⁸, or R^(5a) is O, R⁶ is a bond, and R⁷ is selected from the group consisting of OH, C₁₋₈alkoxy, and haloC₁₋₈alkoxy;

T¹, T², T³, and T⁴ are independently C or N provided that at least one of T¹, T², T³, and T⁴ is N and at least one of T¹, T², T³, and T⁴ is C;

each R^(a) is independently selected from the group consisting of halo, R^(b), OR^(d), O(CH₂)_(u)OR^(d), O(CH₂)_(u)NR^(d)R^(d), O(CH₂)_(u)NR^(d)C(O)R^(e), O(CH₂)_(u)NR^(d)C(O)₂R^(c), O(CH₂)_(u)NR^(d)S(O)₂R^(e), NH₂, —(CH₂)_(k)OC(O)R^(c), —(CH₂)_(k)SR^(d), CN, NO₂, —(CH₂)_(k)CO₂(C₁₋₈alkyl)OH, —(CH₂)_(k)CO₂(C₁₋₈alkyl)(heteroaryl)C(O)(C₁₋₈alkyl), —(CH₂)_(k)CO₂R^(d), —(CH₂)CONR^(d)R^(d), —(CH₂)_(k)NR^(d)C(O)R^(c), —(CH₂)_(k)NR^(d)C(O)₂R^(c), —(CH₂)_(k)C(O)R^(d), —(CH₂)_(k)OC(O)NR^(d)R^(d), —NR^(d)(CH₂)_(u)OR^(d), —NR^(d)(CH₂)_(u)NR^(d)R^(d), —NR^(d)(CH₂)_(u)NR^(d)C(O)R^(c), —NR^(d)(CH₂)_(u)NR^(d)C(O)₂R^(e), —NR^(d)(CH₂)_(u)NR^(d)S(O)₂R^(e), —(CH₂)_(k)NR^(d)C(O)R^(e), —(CH₂)_(k)NR^(d)C(O)₂R^(e), —(CH₂)_(k)NR^(d)C(O)NR^(d)R^(d), —(CH₂)_(k)S(O)R^(c), —(CH₂)_(k)S(O)₂R^(e), —(CH₂)_(k)NR^(d)S(O)₂R^(e), —C(O)(CH₂)_(k)NR^(d)S(O)₂R^(e), —(CH₂)_(k)C(O)NR^(d)S(O)₂R^(c), —(CH₂)_(k)S(O)₂NR^(d)R^(d), N₃, —(CH₂)_(k)aryl optionally substituted with one to three R^(c), —NR^(d)(CH₂)_(k)aryl optionally substituted with one to three R^(c), —(CH)_(k)heteroaryl optionally substituted with one to three R^(c), —NR^(d)(CH₂)_(k)heteroaryl optionally substituted with one to three R^(c), —(CH₂)_(k)heterocycloalkyl optionally substituted with one to three R^(c), and —NR^(d)(CH₂)_(k)heterocycloalkyl optionally substituted with one to three R^(c) where k is 0, 1, 2, 3, 4, 5, or 6 and u is 1, 2, 3, 4, 5, or 6;

each R^(b) is independently selected from the group consisting of C₁₋₈alkyl, C₂₋₈alkenyl, and C₂₋₈alkynyl, each optionally independently substituted with one to three halo, OR^(d), or NR^(d)R^(d);

each R^(c) is independently selected from the group consisting of halo, C₁₋₈alkyl, haloC₁₋₈alkyl, C₂₋₈alkenyl, haloC₂₋₈alkenyl, C₂₋₈alkynyl, haloC₂₋₈alkynyl, (CH₂)_(m)OR^(f), OC(O)R^(g), SR^(f), CN, NO₂, (CH₂)_(m)CO₂R^(f), CONR^(f)R^(f), C(O)R^(f), OC(O)NR^(f)R^(f), (CH₂)_(m)NR^(f)R^(f), NR^(f)C(O)R^(g), NR^(f)C(O)₂R^(g), NR^(f)C(O)NR^(f)R^(f), S(O)R^(g), S(O)₂R^(g), NR^(f)S(O)₂R^(g), S(O)₂NR^(f)R^(f), N₃, (R^(f))_(m)SiC₁₋₈alkyl, heteroaryl optionally substituted with one to three R^(h), cycloalkyl optionally substituted with one to three R^(h), and heterocycloalkyl optionally substituted with one to three R^(h) where m is selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6;

each R^(h) is independently selected from the group consisting of halo, C₁₋₈alkyl, haloC₁₋₈alkyl, OR^(j), OC(O)R, SR^(j), NO₂, CO₂R^(j), CONR^(j)R^(j), C(O)R^(j), OC(O)NR^(j)R^(j), NR^(j)R^(j), NR^(j)C(O)R^(t), NR^(j)C(O)₂R^(t), NR^(j)C(O)NR^(j)R^(j), S(O)R^(t), S(O)₂R^(t), NR^(j)S(O)₂R^(t), and S(O)₂NR^(j)R^(j);

R^(d), R^(f), and R^(j) are each independently selected from the group consisting of hydrogen, C₁₋₈ alkyl, haloC₁₋₈alkyl, C₂₋₈ alkenyl, haloC₂₋₈alkenyl, C₂₋₈ alkynyl, and haloC₂₋₈alkynyl; and

R^(c), R^(g), and R^(t) are each independently selected from the group consisting of C₁₋₈alkyl, haloC₁₋₈alkyl, C₂₋₈ alkenyl, haloC₂₋₈alkenyl, C₂₋₈ alkynyl, and haloC₂₋₈alkynyl.

In one group of embodiments, X and Y are not both O.

In one group of embodiments, when X is O, R^(1b) is not OH.

In one group of embodiments, when Y is O, and n is 0, R⁸ is not OH.

In one group of embodiments, z is 0. In another group of embodiments, z is 1. In yet another group of embodiments, z is 2. In still another group of embodiments, z is 3.

In one group of embodiments, when R⁶ and R⁷ together are oxo, Y is CH₂, X is O or CH₂, and R⁵ is H, halo, OH, CHO, or OCH₃, then Q is V or W.

In one group of embodiments, the compound is not

In one group of embodiments, provided is a compound of Formula (Ia):

or a tautomer or pharmaceutically acceptable salt thereof,

wherein Q is selected from the group consisting of aryl, heteroaryl, and heterocycloalkyl, each optionally substituted with one to three R^(a);

Y is O or CR^(1a)R^(1b), where R^(1a) is H or halo and R^(1b) is selected from the group consisting of H, halo, and OH;

X is selected from the group consisting of O, >CH(CH₂)_(n)R⁸, and C(R⁹)₂ where n is 0 or 1, R⁸ is OH, and R⁹ is independently H or halo; or Y—X taken together is —NHC(O)— or —C(O)NH—;

R², R³, R⁴, and R⁵ are independently absent or selected from the group consisting of hydrogen, halo, R^(b), OR^(d), OC(O)R^(c), SR^(d), CN, NO₂, CO₂R^(d), CONR^(d)R^(d), C(O)R^(d), OC(O)NR^(d)R^(d), NR^(d)R^(d), NR^(d)C(O)R^(e), NR^(d)C(O)₂R^(e), NR^(d)C(O)NR^(d)R^(d), S(O)R^(c), S(O)₂R^(e), NR^(d)S(O)₂R^(e), S(O)₂NR^(d)R^(d), and N₃; or R⁵ is —(CH₂)_(p)R^(5a) where p is 0 or 1 and R^(5a) is OH;

R⁶ and R⁷ together form oxo or an aldehyde protecting group, or R⁶ together with R^(1b), R⁸, or R⁵ forms a cyclic ether where one of R^(1b), R⁸, or R^(5a) is O, R⁶ is a bond, and R⁷ is selected from the group consisting of OH, C₁₋₈alkoxy, and haloC₁₋₈alkoxy;

T¹, T², T³, and T⁴ are independently C or N provided that at least one of T¹, T², T³, and T⁴ is N and at least one of T¹, T², T³, and T⁴ is C;

each R^(a) is independently selected from the group consisting of halo, R^(b), OR^(d), OC(O)R^(e), SR^(d), CN, NO₂, CO₂R^(d), CONR^(d)R^(d), C(O)R^(d), OC(O)NR^(d)R^(d), NR^(d)C(O)R^(e), NR^(d)C(O)₂R^(d), NR^(d)C(O)NR^(d)R^(d), S(O)R^(e), S(O)₂R^(e), NR^(d)S(O)₂R^(e), S(O)₂NR^(d)R^(d), N₃, aryl optionally substituted with one to three R^(c), heteroaryl optionally substituted with one to three R^(c), and heterocycloalkyl optionally substituted with one to three R^(c);

each R^(b) is independently selected from the group consisting of C₁₋₈alkyl, C₂₋₈alkenyl, and C₂₋₈alkynyl, each optionally independently substituted with one to three halo, OR^(d), or NR^(d)R^(d);

each R^(c) is independently selected from the group consisting of halo, C₁₋₈alkyl, haloC₁₋₈alkyl, C₂₋₈alkenyl, haloC₂₋₈alkenyl, C₂₋₈alkynyl, haloC₂₋₈alkynyl, (CH₂)_(m)OR^(f), OC(O)R^(g), SR^(f), CN, NO₂, CO₂R^(f), CONR^(f)R^(f), C(O)R^(f), OC(O)NR^(f)R^(f), (CH₂)_(m)NR^(f)R^(f), NR^(f)C(O)R^(g), NR^(f)C(O)₂R^(g), NR^(f)C(O)NR^(f)R^(f), S(O)R^(g), S(O)₂R^(g), NR^(f)S(O)₂R^(g), S(O)₂NR^(f)R^(f), and N₃ where m is selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6;

each R^(d) and R^(f) is independently selected from the group consisting of hydrogen, C₁₋₈alkyl, haloC₁₋₈alkyl, C₂₋₈alkenyl, haloC₂₋₈alkenyl, C₂₋₈alkynyl, and haloC₂₋₈alkynyl; and

each R^(e) and R^(g) is independently selected from the group consisting of C₁₋₈alkyl, haloC₁₋₈alkyl, C₂₋₈ alkenyl, haloC₂₋₈alkenyl, C₂₋₈ alkynyl, and haloC₂₋₈alkynyl;

provided that X and Y are not both O;

provided that when X is O, R^(1b) is not OH;

provided that when Y is O, and n is 0, R⁸ is not OH.

In one group of embodiments, the compound is not:

In one group of embodiments, provided is a compound having Formula (Ia)

or a tautomer or pharmaceutically acceptable salt thereof.

In one group of embodiments, provided is a compound having Formula (Ib):

or a tautomer or pharmaceutically acceptable salt thereof.

In one group of embodiments, provided is a compound having Formula (Ic):

or a tautomer or pharmaceutically acceptable salt thereof.

In one group of embodiments, provided is a compound having Formula (Id):

or a tautomer or pharmaceutically acceptable salt thereof.

In one group of embodiments, at least two of T¹, T², T³, and T⁴ are N.

In one group of embodiments, provided is a compound having Formula (Ie), (If), (Ig), or (Ih):

or a tautomer or pharmaceutically acceptable salt thereof.

In one group of embodiments, provided is a compound having Formula (If):

or a tautomer or pharmaceutically acceptable salt thereof.

In one group of embodiments, provided is a compound having Formula (Ig):

or a tautomer or pharmaceutically acceptable salt thereof.

In one group of embodiments, provided is a compound having Formula (h):

or a tautomer or pharmaceutically acceptable salt thereof.

In one group of embodiments, R⁶ and R⁷ together form oxo.

In one group of embodiments, R⁶ and R⁷ together form a thiazolidine.

In one group of embodiments, R⁶ together with R^(1b), R⁸, or R⁵ forms a cyclic ether where one of R^(1b), R⁸, or R^(5a) is O, R⁶ is a bond, and R⁷ is selected from the group consisting of OH, C₁₋₈alkoxy, and haloC₁₋₈alkoxy.

In one group of embodiments, provided is a compound having Formula (Ii):

or a tautomer or pharmaceutically acceptable salt thereof, wherein R¹⁰ is selected from the group consisting of H, C₁₋₈alkyl, and haloC₁₋₈alkyl.

In one group of embodiments, provided is a compound having Formula (Ij):

or a tautomer or pharmaceutically acceptable salt thereof, wherein R¹⁰ is selected from the group consisting of H, C₁₋₈alkyl, and haloC₁₋₈alkyl.

In one group of embodiments, provided is a compound having Formula (Ik):

or a tautomer or pharmaceutically acceptable salt thereof, wherein R¹⁰ is selected from the group consisting of H, C₁₋₈alkyl, and haloC₁₋₈alkyl.

In one group of embodiments, provided is a compound having Formula (Il):

or a tautomer or pharmaceutically acceptable salt thereof.

In one group of embodiments, provided is a compound having Formula (Im):

or a tautomer or pharmaceutically acceptable salt thereof.

In one group embodiments, at least one R^(a) is heteroaryl optionally substituted with one to three R^(c).

In one group of embodiments at least one R^(a) is heteroaryl attached to Q at the ring atom adjacent to ring atom bearing Y.

In one group of embodiments at least one R^(a) is heteroaryl substituted with at least one C₁₋₈alkyl. In one group of embodiments at least one R^(a) heteroaryl is substituted with at least one methyl.

In one group of embodiments at least one R^(a) is pyrazolyl substituted with at least one C₁₋₈alkyl. In one group of embodiments at least one R^(a) is pyrazoyl substituted with at least one C₁₋₈alkyl. In one group of embodiments, at least one R^(a) is pyrazol-5-yl. In one group of embodiments, at least one R^(a) is 4-methyl-pyrazol-5-yl.

In one group of embodiments, Q is a heteroaryl or heterocycloalkyl group optionally substituted with one to three R^(a).

In one group of embodiments, Q is a bicyclic heteroaryl or heterocycloalkyl group optionally substituted with one to three R^(a).

In one group of embodiments, Q is a bicyclic heteroaryl group optionally substituted with one to three R^(a).

In one group of embodiments, Q is a bicyclic heteroaryl group substituted with one to three R^(a). In one group of embodiments, Q is isoquinolin-4-yl optionally substituted with one to three R^(a) wherein at least one R^(a) is heteroaryl optionally substituted with one to three R^(c). In one group of embodiments at least one R^(a) is heteroaryl attached to said Q at the ring atom adjacent to ring atom bearing Y. In one group of embodiments at least one R^(a) is heteroaryl substituted with at least one C₁₋₈alkyl. In one group of embodiments at least one R^(a) heteroaryl is substituted with at least one methyl. In one group of embodiments at least one R^(a) is pyrazolyl substituted with at least one C₁₋₈alkyl. In one group of embodiments at least one R^(a) is pyrazoyl substituted with at least one methyl. In one group of embodiments, R is pyrazol-5-yl. In one group of embodiments, R^(a) is 4-methyl-pyrazol-5-yl.

In one group of embodiments, Q is selected from the group consisting of

and naphthalene containing two to four ring nitrogen atoms, each optionally substituted with one to three R^(a) and wherein the wavy line signifies the point of attachment to Y.

In one group of embodiments, Q is selected from the group consisting of

wherein Q is optionally substituted with one to three R^(a).

In one group of embodiments, Q is selected from the group consisting of

In one group of embodiments, Q is substituted with CONR^(d)R^(d), NR^(d)R^(d), or heteroaryl optionally substituted with one to three R^(c). In one group of embodiments, Q is substituted with heteroaryl having one to two nitrogen ring atoms.

In one group of embodiments, Q is not unsubstituted pyridin-2-yl, unsubstituted pyridin-3-yl, or unsubstituted pyridine-4-yl. In one group of embodiments, Q is pyridin-2-yl, pyridin-3-yl, or pyridine-4-yl, each of which is substituted with one to three R^(c).

In one group of embodiments, Q is pyridin-2-yl, pyridin-3-yl, or pyridine-4-yl, said Q is optionally substituted with CN or CONR^(d)R^(d).

In one group of embodiments, Q is pyridin-2-yl, pyridin-3-yl, or pyridine-4-yl, said Q is optionally substituted with one to three R^(a) wherein at least one R is heteroaryl optionally substituted with one to three R^(c). In one group of embodiments at least one R^(a) is heteroaryl attached to said Q at the ring atom adjacent to ring atom bearing Y. In one group of embodiments at least one R^(a) is heteroaryl substituted with at least one C₁₋₈alkyl. In one group of embodiments at least one R^(a) heteroaryl is substituted with at least one methyl. In one group of embodiments at least one R^(a) is pyrazolyl substituted with at least one C₁₋₈alkyl. In one group of embodiments at least one R^(a) is pyrazoyl substituted with at least one methyl. In one group of embodiments, R^(a) is pyrazol-5-yl. In one group of embodiments, R^(a) is 4-methyl-pyrazol-5-yl.

In one group of embodiments, Q is substituted with at least one R^(a) selected from the group consisting of —(CH₂)_(k)OH, —(CH₂)_(k)NH₂, —(CH₂)_(k)NH(C₁₋₈alkyl), —(CH₂)_(k)N(C₁₋₈alkyl)(C₁₋₈alkyl), —(CH₂)_(k)NHC(O)(C₁₋₈alkyl), —(CH₂)_(k)N(C₁₋₈alkyl)C(O)(C₁₋₈alkyl), —(CH₂)_(k)NHC(O)₂(C₁₋₈alkyl), —(CH₂)_(k)N(C₁₋₈alkyl)C(O)₂(C₁₋₈alkyl), —(CH₂)_(k)NHS(O)₂(C₁₋₈alkyl), —(CH₂)_(k)N(C₁₋₈alkyl)S(O)₂(C₁₋₈alkyl), and —(CH₂)_(k)heterocycloalkyl optionally substituted with one to three R^(c) where k is selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6. In some embodiments the heterocycloalkyl group is morpholino or piperazinyl optionally substituted with alkyl, —C(O)C₁₋₈alkyl, —C(O)₂C₁₋₈alkyl, or —S(O)₂C₁₋₈alkyl.

In one group of embodiments, Q is substituted with at least one R^(a) selected from the group consisting of —NR^(d)(CH₂)_(k)OH, —NR^(d)(CH₂)_(k)NH₂, —NR^(d)(CH₂)_(k)NH(C₁₋₈alkyl), —NR^(d)(CH₂)_(k)N(C₁₋₈alkyl)(C₁₋₈alkyl), —NR^(d)(CH₂)_(k)NHC(O)(C₁₋₈alkyl), —NR^(d)(CH₂)_(k)N(C₁₋₈alkyl)C(O)(C₁₋₈alkyl), —NR^(d)(CH₂)_(k)NHC(O)₂(C₁₋₈alkyl), —NR^(d)(CH₂)_(k)N(C₁₋₈alkyl)C(O)₂(C₁₋₈alkyl), —NR^(d)(CH₂)_(k)NHS(O)₂(C₁₋₈alkyl), —NR^(d)(CH₂)_(k)N(C₁₋₈alkyl)S(O)₂(C₁₋₈alkyl), and —NR^(d)(CH₂)_(k)heterocycloalkyl optionally substituted with one to three R^(c) where k is selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6. In some embodiments, R^(d) is H or C₁₋₈alkyl. In some embodiments the heterocycloalkyl group is morpholino or piperazinyl optionally substituted with alkyl, —C(O)C₁₋₈alkyl, —C(O)₂C₁₋₈alkyl, or —S(O)C₁₋₈alkyl.

In one group of embodiments, Q is substituted with at least one R^(a) selected from the group consisting of O(CH₂)_(k)OH, O(CH₂)_(k)NH₂, O(CH₂)_(k)NH(C₁₋₈alkyl), O(CH₂)_(k)N(C₁₋₈alkyl)(C₁₋₈alkyl), O(CH₂)_(k)NHC(O)(C₁₋₈alkyl), O(CH₂)_(k)N(C₁₋₈alkyl)C(O)(C₁₋₈alkyl), O(CH₂)_(k)NHC(O)₂(C₁₋₈alkyl), O(CH₂)_(k)N(C₁₋₈alkyl)C(O)₂(C₁₋₈alkyl), O(CH₂)_(k)NHS(O)₂(C₁₋₈alkyl), O(CH₂)_(k)N(C₁₋₈alkyl)S(O)₂(C₁₋₈alkyl), and O(CH₂)_(k)heterocycloalkyl optionally substituted with one to three R^(c) where k is selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6. In some embodiments the heterocycloalkyl group is morpholino or piperazinyl optionally substituted with alkyl, —C(O)C₁₋₈alkyl, —C(O)₂C₁₋₈alkyl, or —S(O)₂C₁₋₈alkyl.

In one group of embodiments, T¹ is C and R² is H.

In one group of embodiments, T² is C and R³ is H.

In one group of embodiments, T⁴ is C and R⁵ is H.

In one group of embodiments, T³ is C and R⁴ is C₁₋₈ alkoxy.

In one group of embodiments, R², R³, R⁵ when present are H and R⁴ is C₁₋₈ alkoxy.

In one group of embodiments, R⁴ is methoxy.

In one group of embodiments, R⁴ is haloalkoxy. In one group of embodiments, R⁴ is OCHF₂. In one group of embodiments, R⁴ is OCF₃.

In one group of embodiments, R², R³, R⁴, and R⁵ when present are H.

In one group of embodiments, one of R², R³, R⁴, and R⁵ is selected from the group consisting of —O(CH₂)_(z)OH, —O(CH₂)_(z)NH₂, —O(CH₂)_(z)NH(C₁₋₈alkyl), and —O(CH₂)_(z)N(C₁₋₈alkyl)(C₁₋₈alkyl) where z is selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6.

In one group of embodiments, X is O.

In one group of embodiments, CH₂.

In one group of embodiments, X is C(R⁹)₂ and at least one of R⁹ is F.

In one group of embodiments, Y is CH₂.

In one group of embodiments, Y is CR^(1a)R^(1b) and at least one of R^(1a) or R^(1b) is F.

In one group of embodiments, the compound is not:

In another group of embodiments, the invention provides compounds of Formula (Ib):

or a tautomer or pharmaceutically acceptable salt thereof, wherein:

Q is selected from the group consisting of aryl, heteroaryl, and heterocycloalkyl, each optionally substituted with one to three R^(a);

Y is O or CH₂;

X is O or CH₂;

R² and R³ are independently absent or selected from the group consisting of hydrogen, halo, R^(b), OR^(d), O(CH₂)_(z)OR^(d), O(CH₂)_(z)NR^(d)R^(d), OC(O)R^(c), SR^(d), CN, NO₂, CO₂R^(d), CONR^(d)R^(d), C(O)R^(d), OC(O)NR^(d)R^(d), NR^(d)R^(d), NR^(d)C(O)R^(e), NR^(d)C(O)₂R^(e), NR^(d)C(O)NR^(d)R^(d), S(O)R^(e), S(O)₂R^(e), NR^(d)S(O)₂R^(e), S(O)₂NR^(d)R^(d), and N₃ where z is 0, 1, 2, or 3;

R⁴ is absent or selected from the group consisting of hydrogen, R^(b), OR^(d), O(CH₂)_(z)OR^(d), where z is 0, 1, 2, or 3;

R⁵ is absent or selected from the group consisting of hydrogen, halo, R^(b), and OR^(d);

R⁶ and R⁷ together form oxo or an aldehyde protecting group;

T¹, T², T³, and T⁴ are independently C or N provided that at least one of T¹, T², T³, and T⁴ is N and at least one of T¹, T², T³, and T⁴ is C;

each R^(a) is independently selected from the group consisting of halo, oxo, R^(b), OR^(d), O(CH₂)_(u)OR^(d), O(CH₂)_(u)NR^(d)R^(d), O(CH₂)_(u)NR^(d)C(O)R^(e), O(CH₂)_(u)NR^(d)C(O)₂R^(e), O(CH₂)_(u)NR^(d)S(O)₂R^(e), NH₂, —(CH₂)_(k)OC(O)R^(e), —(CH₂)_(k)SR^(d), CN, NO₂, —(CH₂)_(k)CO₂(C₁₋₈alkyl)OH, —(CH₂)_(k)CO₂(C₁₋₈alkyl)(heteroaryl)C(O)(C₁₋₈alkyl), —(CH₂)_(k)CO₂R^(d), —(CH₂)_(k)CONR^(d)R^(d), —(CH₂)_(k)NR^(d)C(O)R^(e), —(CH₂)_(k)NR^(d)C(O)₂R^(e), —(CH₂)_(k)C(O) R^(d), —(CH₂)_(k)OC(O)NR^(d)R^(d), —NR^(d)(CH₂)_(u)OR^(d), —NR^(d)(CH₂)_(u)NR^(d)R^(d), —NR^(d)(CH₂)_(u)NR^(d)C(O)R^(e), —NR^(d)(CH₂)_(u)NR^(d)C(O)₂R^(e), —NR^(d)(CH₂)_(u)NR^(d)S(O)₂R^(e), —(CH₂)_(k)NR^(d)C(O)R^(e), —(CH₂)_(k)NR^(d)C(O)₂R^(d), —(CH₂)_(k)NR^(d)C(O)NR^(d)R^(d), —(CH₂)_(k)S(O)R^(c), —(CH₂)_(k)S(O)₂R^(e), —(CH₂)_(k)NR^(d)S(O)₂R^(e), —C(O)(CH₂)_(k)NR^(d)S(O)₂R^(e), —(CH₂)_(k)C(O)NR^(d)S(O)₂R^(c), —(CH₂)_(k)S(O)₂NR^(d)R^(d), N₃, —(CH₂)_(k)aryl optionally substituted with one to three R^(c), —NR^(d)(CH₂)_(k)aryl optionally substituted with one to three R^(c), —(CH₂)_(k)heteroaryl optionally substituted with one to three R^(c), —NR^(d)(CH₂)_(k)heteroaryl optionally substituted with one to three R^(c), —(CH₂)_(k)heterocycloalkyl optionally substituted with one to three R^(c), and —NR^(d)(CH₂)_(k)heterocycloalkyl optionally substituted with one to three R^(c) where k is 0, 1, 2, 3, 4, 5, or 6 and u is 1, 2, 3, 4, 5, or 6;

each R^(b) is independently selected from the group consisting of C₁₋₈alkyl, C₂₋₈alkenyl, and C₂₋₈alkynyl, each optionally independently substituted with one to three halo, OR^(d), or NR^(d)R^(d);

each R^(c) is independently selected from the group consisting of halo, C₁₋₈alkyl, haloC₁₋₈alkyl, C₂₋₈alkenyl, haloC₂₋₈alkenyl, C₂₋₈alkynyl, haloC₂₋₈alkynyl, (CH₂)_(m)OR^(f), OC(O)R^(g), SR^(f), CN, NO₂, (CH₂)_(m)CO₂R^(f), CONR^(f)R^(f), C(O)R^(f), OC(O)NR^(f)R^(f), (CH₂)_(m)NR^(f)R^(f), NR^(f)C(O)R^(g), NR^(f)C(O)₂R^(g), NR^(f)C(O)NR^(f)R^(f), S(O)R^(g), S(O)₂R^(g), NR^(f)S(O)₂R^(g), S(O)₂NR^(f)R^(f), N₃, (R^(f))_(m)SiC₁₋₈alkyl, heteroaryl optionally substituted with one to three R^(h), cycloalkyl optionally substituted with one to three R^(h), and heterocycloalkyl optionally substituted with one to three R^(h) where m is selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6;

each R^(h) is independently selected from the group consisting of halo, C₁₋₈alkyl, haloC₁₋₈alkyl, OR^(j), OC(O)R, SR^(j), NO₂, CO₂R^(j), CONR^(j)R^(j), C(O)R^(j), OC(O)NR^(j)R^(j), NR^(j)R^(j), NR^(j)C(O)R^(t), NR^(j)C(O)₂R^(t), NR^(j)C(O)NR^(j)R^(j), S(O)R^(t), S(O)₂R^(t), NR^(j)S(O)₂R^(t), and S(O)₂NR^(j)R^(j);

R^(d), R^(f), and R^(j) are each independently selected from the group consisting of hydrogen, C₁₋₈ alkyl, haloC₁₋₈alkyl, C₂₋₈ alkenyl, haloC₂₋₈alkenyl, C₂₋₈ alkynyl, and haloC₂₋₈alkynyl; and

R^(e), R^(g), and R^(t) are each independently selected from the group consisting of C₁₋₈alkyl, haloC₁₋₈alkyl, C₂₋₈ alkenyl, haloC₂₋₈alkenyl, C₂₋₈ alkynyl, and haloC₂₋₈alkynyl;

provided that X and Y are not both O;

provided that when Q is phenyl and R⁴ is C₁₋₈alkyl or C₂₋₈alkenyl, Q is substituted with at least one R^(a);

provided that when R⁵ is halo, Q is substituted with at least 1 R^(a);

provided that when R⁵ is R^(b), Q is not phenyl; and

provided that when R², R³, R⁴, and R⁵ are H and Q is phenyl, Q is substituted with at least one R^(a) selected from 4-carboxy, 3-carboxy, and (C₁₋₈ alkyl 3-carboxylate).

In one group of embodiments, the invention provides compounds of Formula Ib wherein R² and R³ are independently absent or selected from the group consisting of hydrogen, R^(b), OR^(d), O(CH₂)_(z)OR^(d), O(CH₂)_(z)NR^(d)R^(d), OC(O)R^(e), CO₂R^(d), CONR^(d)R^(d), and C(O)R^(d), where z is 1, 2, or 3.

In one group of embodiments, the invention provides compounds of Formula Ib wherein at least one z is 0. In another group of embodiments, at least one z is 1. In yet another group of embodiments, at least one z is 2. In still another group of embodiments, at least one z is 3. In another group of embodiments, no z is 0.

In one group of embodiments, the invention provides compounds of Formula Ib wherein T² is N; T¹, T³, and T⁴ are C; R² and R⁵ are H; R³ is absent; and R⁴ is C₁₋₈alkoxy.

In one group of embodiments, the invention provides compounds of Formula Ib wherein T² is N; T¹, T³, and T⁴ are C; R² and R⁵ are H; R³ is absent; and R⁵ is selected from hydroxy and C₁₋₈alkoxy.

In one group of embodiments, the invention provides compounds of Formula Ib wherein T⁴ is N; T¹, T², and T³ are C; R² and R³ are H; R⁵ is absent; and R⁴ is selected from C₁₋₈alkyl and C₁₋₈alkoxy.

In one group of embodiments, the invention provides compounds of Formula Ib wherein T¹ is N; T², T³, and T⁴ are C; R³, R⁴, and R³ are H; and R² is absent.

In one group of embodiments, the invention provides compounds of Formula Ib wherein T² is N; T¹, T³, and T⁴ are C; R², R⁴, and R⁵ are H; and R³ is absent.

In one group of embodiments, the invention provides compounds of Formula Ib wherein T³ is N; T¹, T², and T⁴ are C; R², R³, and R⁵ are H; and R⁴ is absent.

In one group of embodiments, the invention provides compounds of Formula Ib wherein T⁴ is N; T¹, T², and T³ are C; R², R³, and R⁴ are H; and R⁵ is absent.

In one group of embodiments, the invention provides compounds of Formula Ib wherein Q is selected from an imidazopyridinyl group, a pyrrolopyridinyl group, a pyrazolopyridinyl group, a triazolopyridinyl group, a pyrazolopyrazinyl group, a pyridinyl group, a pyrazinyl group, an oxazolyl group, an imidazolyl group, a triazolyl group, a tetrazolyl group, a pyrazolyl group, a quinolinyl group, an isoquinolinyl group, an indazolyl group, a benzooxazolyl group, a naphthyridinyl group, and a quinoxalinyl group; and wherein Q is optionally substituted with one to three R^(a).

In another group of embodiments, the invention provides compounds of Formula Ic:

or a tautomer or pharmaceutically acceptable salt thereof, wherein:

Y is CH₂;

X is O or CH₂;

T¹, T², T³, and T⁴ are C or N, provided that no more than one of T¹, T², T³, and T⁴ is N;

Q is selected from the group consisting of

i) heteroaryl optionally substituted with one to three R^(a); wherein

-   -   R², R³, R⁴, and R⁵, are independently absent or selected from         the group consisting of hydrogen, halo, R^(b), OR^(d),         O(CH₂)_(z)OR^(d), O(CH₂)_(z)NR^(d)R^(d), OC(O)R^(e), SR^(d), CN,         NO₂, CO₂R^(d), CONR^(d)R^(d), C(O)R^(d), OC(O)NR^(d)R^(d),         NR^(d)R^(d), NR^(d)C(O)R^(e), NR^(d)C(O)₂R^(e),         NR^(d)C(O)NR^(d)R^(d), S(O)R^(e), S(O)₂R^(e), NR^(d)S(O)₂R^(e),         S(O)₂NR^(d)R^(d), and N₃ where z is 0, 1, 2, or 3;

ii) aryl substituted with one to three —(CH₂)_(k)CO₂R^(d); wherein

-   -   R² and R⁵ are independently absent or selected from the group         consisting of hydrogen, halo, OR^(d), O(CH₂)_(z)OR^(d),         O(CH₂)_(z)NR^(d)R^(d), OC(O)R^(e), SR^(d), CN, NO₂, CO₂R^(d),         CONR^(d)R^(d), C(O)R^(d), OC(O)NR^(d)R^(d), NR^(d)R^(d),         NR^(d)C(O)R^(e), NR^(d)C(O)₂R^(e), NR^(d)C(O)NR^(d)R^(d),         S(O)R^(e), S(O)₂R^(e), NR^(d)S(O)₂R^(e), S(O)₂NR^(d)R^(d), and         N₃ where z is 0, 1, 2, or 3;     -   R³ and R⁴ are independently absent or selected from the group         consisting of hydrogen, halo, R^(b), OR^(d), O(CH₂)_(z)OR^(d),         O(CH₂)_(z)NR^(d)R^(d), OC(O)R^(e), SR^(d), CN, NO₂, CO₂R^(d),         CONR^(d)R^(d), C(O)R^(d), OC(O)NR^(d)R^(d), NR^(d)R^(d),         NR^(d)C(O)R^(e), NR^(d)C(O)₂R^(e), NR^(d)C(O)NR^(d)R^(d),         S(O)R^(e), S(O)₂R^(e), NR^(d)S(O)₂R^(e), S(O)₂NR^(d)R^(d), and         N₃ where z is 0, 1, 2, or 3;

iii) unsubstituted aryl, wherein

-   -   R², R³, and R⁴, are independently absent or selected from the         group consisting of hydrogen, halo, R^(b), OR^(d),         O(CH₂)_(z)OR^(d), O(CH₂)_(z)NR^(d)R^(d), OC(O)R^(e), SR^(d), CN,         NO₂, CO₂R^(d), CONR^(d)R^(d), C(O)R^(d), OC(O)NR^(d)R^(d),         NR^(d)R^(d), NR^(d)C(O)R^(e), NR^(d)C(O)₂R^(e),         NR^(d)C(O)NR^(d)R^(d), S(O)R^(e), S(O)₂R^(e), NR^(d)S(O)₂R^(e),         S(O)₂NR^(d)R^(d), and N₃ where z is 0, 1, 2, or 3; and     -   R⁵ is absent or is OR^(d); and

iv) heterocycloalkyl, optionally substituted with one to three R⁵; wherein

-   -   R², R³, R⁴, and R⁵, are independently absent or selected from         the group consisting of hydrogen, R^(b), OR^(d),         O(CH₂)_(z)OR^(d), O(CH₂)_(z)NR^(d)R^(d), OC(O)R^(e), SR^(d), CN,         NO₂, CO₂R^(d), CONR^(d)R^(d), C(O)R^(d), OC(O)NR^(d)R^(d),         NR^(d)R^(d), NR^(d)C(O)R^(e), NR^(d)C(O)₂R^(e),         NR^(d)C(O)NR^(d)R^(d), S(O)R^(e), S(O)₂R^(e), NR^(d)S(O)₂R^(e),         S(O)₂NR^(d)R^(d), and N₃ where z is 0, 1, 2, or 3;

R⁶ and R⁷ together form oxo or an aldehyde protecting group;

each R^(a) is independently selected from the group consisting of halo, oxo, R^(b), OR^(d), O(CH₂)_(u)OR^(d), O(CH₂)_(u)NR^(d)R^(d), O(CH₂)_(u)NR^(d)C(O)R^(e), O(CH₂)_(u)NR^(d)C(O)₂R^(e), O(CH₂)_(u)NR^(d)S(O)₂R^(e), NH₂, —(CH₂)_(k)OC(O)R^(e), —(CH₂)_(k)SR^(d), CN, NO₂, —(CH₂)_(k)CO₂(C₁₋₈alkyl)OH, —(CH₂)_(k)CO₂(C₁₋₈alkyl)(heteroaryl)C(O)(C₁₋₈alkyl), —(CH₂)_(k)CO₂R^(d), —(CH₂)_(k)CONR^(d)R^(d), —(CH₂)_(k)NR^(d)C(O)R^(e), —(CH₂)_(k)NR^(d)C(O)₂R^(e), —(CH₂)_(k)C(O)R^(d), —(CH₂)_(k)OC(O)NR^(d)R^(d), —NR^(d)(CH₂)_(u)OR^(d), —NR^(d)(CH₂)_(u)NR^(d)R^(d), —NR^(d)(CH₂)_(u)NR^(d)C(O)R^(e), —NR^(d)(CH₂)_(u)NR^(d)C(O)₂R^(e), —NR^(d)(CH₂)_(u)NR^(d)S(O)₂R^(e), —(CH₂)_(k)NR^(d)C(O)R^(e), —(CH₂)_(k)NR^(d)C(O)₂R^(d), —(CH₂)_(k)NR^(d)C(O)NR^(d)R^(d), —(CH₂)_(k)S(O)R^(e), —(CH₂)_(k)S(O)₂R^(e), —(CH₂)_(k)NR^(d)S(O)₂R^(e), —C(O)(CH₂)_(k)NR^(d)S(O)₂R^(e), —(CH₂)_(k)C(O)NR^(d)S(O)₂R^(e), —(CH₂)_(k)S(O)₂NR^(d)R^(d), N₃, —(CH₂)_(k)aryl optionally substituted with one to three R^(c), —NR^(d)(CH₂)_(k)aryl optionally substituted with one to three R^(c), —(CH₂)heteroaryl optionally substituted with one to three R^(c), —NR^(d)(CH₂)heteroaryl optionally substituted with one to three R^(c), —(CH₂)_(k)heterocycloalkyl optionally substituted with one to three R^(c), and —NR^(d)(CH₂)_(k)heterocycloalkyl optionally substituted with one to three R^(c) where k is 0, 1, 2, 3, 4, 5, or 6 and u is 1, 2, 3, 4, 5, or 6;

each R^(b) is independently selected from the group consisting of C₁₋₈alkyl, C₂₋₈alkenyl, and C₂₋₈alkynyl, each optionally independently substituted with one to three halo, OR^(d), or NR^(d)R^(d);

each R^(c) is independently selected from the group consisting of halo, C₁₋₈alkyl, haloC₁₋₈alkyl, C₂₋₈alkenyl, haloC₂₋₈alkenyl, C₂₋₈alkynyl, haloC₂₋₈alkynyl, (CH₂)_(m)OR^(f), OC(O)R^(g), SR^(f), CN, NO₂, (CH₂)_(m)CO₂R^(f), CONR^(f)R^(f), C(O)R^(f), OC(O)NR^(f)R^(f), (CH₂)_(m)NR^(f)R^(f), NR^(f)C(O)R^(g), NR^(f)C(O)₂R^(g), NR^(f)C(O)NR^(f)R^(f), S(O)R^(g), S(O)₂R^(g), NR^(f)S(O)₂R^(g), S(O)₂NR^(f)R^(f), N₃, (R^(f))_(m)SiC₁₋₈alkyl, heteroaryl optionally substituted with one to three R^(h), cycloalkyl optionally substituted with one to three R^(h), and heterocycloalkyl optionally substituted with one to three R^(h) where m is selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6;

each R^(h) is independently selected from the group consisting of halo, C₁₋₈alkyl, haloC₁₋₈alkyl, OR^(j), OC(O)R, SR^(j), NO₂, CO₂R^(j), CONR^(j)R^(j), C(O)R^(j), OC(O)NR^(j)R^(j), NR^(j)R^(j), NR^(j)C(O)R^(t), NR^(j)C(O)₂R^(t), NR^(j)C(O)NR^(j)R^(j), S(O)R^(t), S(O)₂R^(t), NR^(j)S(O)₂R^(t), and S(O)₂NR^(j)R^(j);

R^(d), R^(t), and R^(j) are each independently selected from the group consisting of hydrogen, C₁₋₈ alkyl, haloC₁₋₈alkyl, C₂₋₈ alkenyl, haloC₂₋₈alkenyl, C₂₋₈ alkynyl, and haloC₂₋₈alkynyl; and

R^(e), R^(g), and R^(t) are each independently selected from the group consisting of C₁₋₈alkyl, haloC₁₋₈alkyl, C₂₋₈ alkenyl, haloC₂₋₈alkenyl, C₂₋₈ alkynyl, and haloC₂₋₈alkynyl.

In one group of embodiments, the invention provides compounds of Formula Ic, wherein R⁶ and R⁷ together form oxo.

In one group of embodiments, the invention provides compounds of Formula Ic, wherein R² and R³ are independently absent or selected from the group consisting of hydrogen, R^(b), OR^(d), O(CH₂)_(z)OR^(d), O(CH₂)_(z)NR^(d)R^(d), OC(O)R^(e), CO₂R^(d), CONR^(d)R^(d), and C(O)R^(d), where z is 1, 2, or 3.

In one group of embodiments, the invention provides compounds of Formula Ic, wherein T² is N; R² and R⁵ are H; R³ is absent; and R⁴ is C₁₋₈alkoxy, haloC₁₋₈alkoxy, and O(CH₂)_(a)C₁₋₈alkyl.

In one group of embodiments, the invention provides compounds of Formula Ic, wherein T² is N; R² and R⁴ are H; R³ is absent; and R⁵ is selected from hydroxy and C₁₋₈alkoxy.

In one group of embodiments, the invention provides compounds of Formula Ic, wherein T⁴ is N; R² and R³ are H; R⁵ is absent; and R⁴ is selected from C₁₋₈alkyl and C₁₋₈alkoxy.

In one group of embodiments, the invention provides compounds of Formula Ic, wherein T¹ is N; R³, R⁴, and R⁵ are H; and R² is absent.

In one group of embodiments, the invention provides compounds of Formula Ic, wherein T² is N; R², R⁴, and R⁵ are H; and R³ is absent.

In one group of embodiments, the invention provides compounds of Formula Ic, wherein T³ is N; R², R³, and R⁵ are H; and R⁴ is absent.

In one group of embodiments, the invention provides compounds of Formula Ic, wherein T⁴ is N; R², R³, and R⁴ are H; and R⁵ is absent.

In one group of embodiments, the invention provides compounds of Formula Ic, or another group of embodiments of Formula Ic that is disclosed herein, wherein Q is selected from the group consisting of an imidazopyridinyl group, a pyrrolopyridinyl group, a pyrazolopyridinyl group, a triazolopyridinyl group, a pyrazolopyrazinyl group, a pyridinyl group, a pyrazinyl group, an oxazolyl group, an imidazolyl group, a triazolyl group, a tetrazolyl group, a pyrazolyl group, a quinolinyl group, an isoquinolinyl group, an indazolyl group, a benzooxazolyl group, a naphthyridinyl group, and a quinoxalinyl group; and wherein Q is optionally substituted with one to three R^(a).

In one group of embodiments, the invention provides compounds of Formula Ic, or another group of embodiments of Formula Ic that is disclosed herein, wherein Q is selected from the group consisting of:

and wherein Q is optionally substituted with one to three R^(a).

In one group of embodiments, the invention provides compounds of Formula Ic wherein at least one z is 0. In another group of embodiments, at least one z is 1. In yet another group of embodiments, at least one z is 2. In still another group of embodiments, at least one z is 3. In another group of embodiments, no z is 0.

In certain embodiments, the compounds of Formula I, Ib and Ic, or tautomers or pharmaceutically acceptable salts thereof, are selected from Table 1 below.

TABLE 1 Compound Structure Name 1

4-(pyridin-3- ylmethoxy)nicotinaldehyde 2

3-(pyridin-3- ylmethoxy)nicotinaldehyde 3

2-(imidazo[1,2-a]pyridin-8- ylmethoxy)nicotinaldehyde 4

3-(imidazo[1,2-a]pyridin-8- ylmethoxy)picolinaldehyde 5

5-(imidazo[1,2-a]pyridin-8- ylmethoxy)-2- methoxyisonicotinaldehyde 6

3-(imidazo[1,2-a]pyridin-8- ylmethoxy)isonicotinaldehyde 7

3-(imidazo[1,5-a]pyridin-8- ylmethoxy)isonicotinaldehyde 8

2-methoxy-5-(pyrazolo[1,5- a]pyrazin-3- ylmethoxy)isonicotinaldehyde 9

8-((3-formylpyridin-2- yloxy)methyl)imidazo[1,2- a]pyridine-6-carboxamide 10

8-((4-formyl-6-methoxypyridin-3- yloxy)methyl)imidazo[1,2- a]pyridine-6-carboxamide 11

5-(imidazo[1,2-a]pyridin-8- ylmethoxy)-2-oxo-1,2- dihydropyridine-4-carbaldehyde 12

2-(2-(imidazo[1,2-a]pyridin-8- yl)ethyl)nicotinaldehyde 13

5-(2-(imidazo[1,2-a]pyridin-8- yl)ethyl)-2- methoxyisonicotinaldehyde 14

5-((1H-pyrazolo[3,4-b]pyridin-4- yl)methoxy)-2- methoxyisonicotinaldehyde 15

3-((4-formyl-6-methoxypyridin-3- yloxy)methyl)pyrazolo[1,5- a]pyrazine-2-carboxamide 16

5-((2-(1H-pyrazol-5- yl)pyrazolo[1,5-a]pyrazin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 17

2-(imidazo[1,2-a]pyridin-2- ylmethoxy)nicotinaldehyde 18

2-methoxy-5-((4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin- 3-yl)methoxy)isonicotinaldehyde 19

2-(imidazo[1,2-a]pyridin-8- ylmethoxy)nicotinaldehyde 20

5-(imidazo[1,2-a]pyridin-8- ylmethoxy)-2- methylisonicotinaldehyde 21

3-((1H-pyrrolo[2,3-b]pyridin-4- yl)methoxy)isonicotinaldehyde 22

3-(imidazo[1,2-a]pyridin-8- ylmethoxy)isonicotinaldehyde 23

3-(pyrrolo[1,2-a]pyrazin-6- ylmethoxy)isonicotinaldehyde 24

6-((4-formylpyridin-3- yloxy)methyl)pyrrolo[1,2- a]pyrazine-7-carbonitrile 25

6-((4-formylpyridin-3- yloxy)methyl)pyrrolo[1,2- a]pyrazine-7-carboxamide 26

3-((1H-pyrazolo[3,4-b]pyridin-4- yl)methoxy)isonicotinaldehyde 27

3-(pyrazolo[1,5-a]pyrazin-3- ylmethoxy)isonicotinaldehyde 28

2-methoxy-5-((6-oxo-1,6- dihydropyridin-3- yl)methoxy)isonicotinaldehyde 29

2-methoxy-5-((2-oxo-1,2- dihydropyridin-4- yl)methoxy)isonicotinaldehyde 30

2-methoxy-5-(oxazol-5- ylmethoxy)isonicotinaldehyde 31

5-((1H-imidazol-5-yl)methoxy)-2- methoxyisonicotinaldehyde 32

5-((1H-imidazol-2-yl)methoxy)-2- methoxyisonicotinaldehyde 33

5-((4H-1,2,4-triazol-3- yl)methoxy)-2- methoxyisonicotinaldehyde 34

5-((1H-tetrazol-5-yl)methoxy)-2- methoxyisonicotinaldehyde 35

5-((1H-pyrazol-5-yl)methoxy)-2- methoxyisonicotinaldehyde 36

5-((1H-pyrazol-4-yl)methoxy)-2- methoxyisonicotinaldehyde 37

2-methoxy-5-(oxazol-4- ylmethoxy)isonicotinaldehyde 38

2-methoxy-5-((2-methylpyridin-3- yl)methoxy)isonicotinaldehyde 39

2-methoxy-5-((4-methylpyridin-3- yl)methoxy)isonicotinaldehyde 40

2-methoxy-5-((6- (trifluoromethyl)pyridin-3- yl)methoxy)isonicotinaldehyde 41

2-methoxy-5-((6-methylpyridin-3- yl)methoxy)isonicotinaldehyde 42

2-methoxy-5-(pyridin-3- ylmethoxy)isonicotinaldehyde 43

2-methoxy-5-((5-methylpyridin-3- yl)methoxy)isonicotinaldehyde 44

5-(isoquinolin-1-ylmethoxy)-2- methoxyisonicotinaldehyde 45

2-methoxy-5-(quinolin-2- ylmethoxy)isonicotinaldehyde 46

2-methoxy-5-(pyridin-4- ylmethoxy)isonicotinaldehyde 47

2-methoxy-5-((3-methylpyridin-4- yl)methoxy)isonicotinaldehyde 48

5-((3-bromopyridin-4- yl)methoxy)-2- methoxyisonicotinaldehyde 49

3-(imidazo[1,2-a]pyridin-8- ylmethoxy)-6- methylpicolinaldehyde 50

(5-(imidazo[1,2-a]pyridin-5- ylmethoxy)-2-methoxypyridin-4- yl)(methoxy)methanol 51

N-(4-formylpyridin-3- yl)imidazo[1,2-a]pyridine-8- carboxamide 52

2-methoxy-5-((6- (trifluoromethyl)imidazo[1,2- a]pyridin-2- yl)methoxy)isonicotinaldehyde 53

methyl 2-((4-formyl-6- methoxypyridin-3- yloxy)methyl)imidazo[1,2- a]pyridine-8-carboxylate 54

2-methoxy-5-((1-methyl-2-oxo- 1,2-dihydropyridin-4- yl)methoxy)isonicotinaldehyde 55

5-((3-bromoimidazo[1,2-a]pyridin- 2-yl)methoxy)-2- methoxyisonicotinaldehyde 56

5-((6-bromoimidazo[1,2-a]pyridin- 2-yl)methoxy)-2- methoxyisonicotinaldehyde 57

5-((8-bromoimidazo[1,2-a]pyridin- 2-yl)methoxy)-2- methoxyisonicotinaldehyde 58

2-methoxy-5-((3-methyl- [1,2,4]triazolo[4,3-a]pyridin-8- yl)methoxy)isonicotinaldehyde 59

5-((3-(1H-pyrazol-5- yl)imidazo[1,2-a]pyridin-2- yl)methoxy)-2- methoxyisonicotinaldehyde 60

5-((6-(1H-pyrazol-3- yl)imidazo[1,2-a]pyridin-2- yl)methoxy)-2- methoxyisonicotinaldehyde 61

2-methoxy-5-((8-(1-methyl-1H- pyrazol-5-yl)imidazo[1,2- a]pyridin-2- yl)methoxy)isonicotinaldehyde 62

5-((4-formyl-6-methoxypyridin-3- yloxy)methyl)picolinonitrile 63

5-((2-bromopyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 64

3-((4-formyl-6-methoxypyridin-3- yloxy)methyl)picolinonitrile 65

5-((2-(1H-pyrazol-5-yl)pyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 66

5-((5-bromopyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 67

methyl 2-((4-(1,3-dioxolan-2-yl)- 6-methoxypyridin-3- yloxy)methyl)imidazo[1,2- a]pyridine-8-carboxylate 68

2-((4-(1,3-dioxolan-2-yl)-6- methoxypyridin-3- yloxy)methyl)imidazo[1,2- a]pyridine-8-carboxamide 69

2-((4-(1,3-dioxolan-2-yl)-6- methoxypyridin-3-yloxy)methyl)- N-methylimidazo[1,2-a]pyridine- 8-carboxamide 70

5-((5-(1H-pyrazol-5-yl)pyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 71

5-((4-(1H-pyrazol-5-yl)pyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 72

2-((4-(dihydroxymethyl)-6- methoxypyridin-3-yloxy)methyl)- N-methylimidazo[1,2-a]pyridine- 8-carboxamide 73

2-((4-(dihydroxymethyl)-6- methoxypyridin-3- yloxy)methyl)imidazo[1,2- a]pyridine-8-carboxamide 74

2-methoxy-5-((5-(1-methyl-1H- pyrazol-5-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 75

2-methoxy-5-((5-(1-methyl-1H- pyrazol-3-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 76

5-((5-(1H-pyrazol-4-yl)pyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 77

2-methoxy-5-((5-(1-methyl-1H- pyrazol-4-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 78

methyl 5-((4-formyl-6- methoxypyridin-3- yloxy)methyl)nicotinate 79

5-((4-formyl-6-methoxypyridin-3- yloxy)methyl)nicotinic acid 80

2-methoxy-5-(quinolin-3- ylmethoxy)isonicotinaldehyde 81

6-methyl-3-(quinolin-3- ylmethoxy)picolinaldehyde 82

5-(isoquinolin-7-ylmethoxy)-2- methoxyisonicotinaldehyde 83

3-(isoquinolin-7-ylmethoxy)-6- methylpicolinaldehyde 84

2-methoxy-5-((1-methyl-1H- indazol-4- yl)methoxy)isonicotinaldehyde 85

6-methyl-3-((1-methyl-1H- indazol-4- yl)methoxy)picolinaldehyde 86

tert-butyl 4-((2-formyl-6- methylpyridin-3-yloxy)methyl)- 1H-indazole-1-carboxylate 87

5-((1H-indazol-4-yl)methoxy)-2- methoxyisonicotinaldehyde 88

3-((1H-indazol-4-yl)methoxy)-6- methylpicolinaldehyde 89

6-methoxy-3-((1-methyl-1H- indazol-6- yl)methoxy)picolinaldehyde 90

2-methoxy-5-((1-methyl-1H- indazol-7- yl)methoxy)isonicotinaldehyde 91

6-methyl-3-((1-methyl-1H- indazol-6- yl)methoxy)picolinaldehyde 92

6-methyl-3-((1-methyl-1H- indazol-7- yl)methoxy)picolinaldehyde 93

3-(isoquinolin-1-ylmethoxy)-6- methylpicolinaldehyde 94

6-methyl-3-(quinolin-2- ylmethoxy)picolinaldehyde 95

5-((4-(1H-pyrazol-4-yl)pyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 96

5-((6-bromoimidazo[1,2-a]pyridin- 8-yl)methoxy)-2- methoxyisonicotinaldehyde 97

8-((4-formyl-6-methoxypyridin-3- yloxy)methyl)imidazo[1,2- a]pyridine-6-carbonitrile 98

5-((4-formyl-6-methoxypyridin-3- yloxy)methyl)nicotinonitrile 99

3-(benzo[d]oxazol-4-ylmethoxy)- 6-methylpicolinaldehyde 100

8-((4-formyl-6-methoxypyridin-3- yloxy)methyl)imidazo[1,2- a]pyridine-6-carboxamide 101

5-((4-formyl-6-methoxypyridin-3- yloxy)methyl)nicotinamide 102

5-((6-(1H-pyrazol-4- yl)imidazo[1,2-a]pyridin-8- yl)methoxy)-2- methoxyisonicotinaldehyde 103

5-(benzo[d]oxazol-4-ylmethoxy)- 2-methoxyisonicotinaldehyde 104

5-((6-(1H-pyrazol-5- yl)imidazo[1,2-a]pyridin-8- yl)methoxy)-2- methoxyisonicotinaldehyde 105

5-((1,5-naphthyridin-4- yl)methoxy)-2- methoxyisonicotinaldehyde 106

3-((1,5-naphthyridin-4- yl)methoxy)-6- methylpicolinaldehyde 107

5-((1H-indazol-5-yl)methoxy)-2- methoxyisonicotinaldehyde 108

6-methyl-3-((1-methyl-1H- indazol-5- yl)methoxy)picolinaldehyde 109

3-((3-chloro-1-methyl-1H-indazol- 5-yl)methoxy)-6- methylpicolinaldehyde 110

2-methoxy-5-((1-methyl-1H- indazol-5- yl)methoxy)isonicotinaldehyde 111

5-((3-chloro-1-methyl-1H-indazol- 5-yl)methoxy-2- methoxyisonicotinaldehyde 112

N-(4-formyl-6-methoxypyridin-3- yl)imidazo[1,2-a]pyridine-8- carboxamide 113

3-((1,3-dimethyl-1H-pyrazolo[3,4- b]pyridin-4-yl)methoxy)-6- methylpicolinaldehyde 114

5-((1,3-dimethyl-1H-pyrazolo[3,4- b]pyridin-4-yl)methoxy)-2- methoxyisonicotinaldehyde 115

3-((4-formyl-6-methoxypyridin-3- yloxy)methyl)picolinamide 116

5-((2-chloroquinolin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 117

5-((2-1H-pyrazol-5-yl)quinolin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 118

2-methoxy-5-(quinoxalin-2- ylmethoxy)isonicotinaldehyde 119

6-methyl-3-(quinolin-5- ylmethoxy)picolinaldehyde 120

2-methoxy-5-(quinolin-5- ylmethoxy)isonicotinaldehyde 121

6-methyl-3-((1-methyl-1H- pyrazolo[3,4-b]pyridin-5- yl)methoxy)picolinaldehyde 122

2-methoxy-5-((1-methyl-1H- pyrazolo[3,4-b]pyridin-5- yl)methoxy)isonicotinaldehyde 123

5-((7-(1H-pyrazol-3- yl)imidazo[1,5-a]pyridin-8- yl)methoxy)-2- methoxyisonicotinaldehyde 124

5-((5-(2H-tetrazol-5-yl)pyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 125

5-((6-(2H-tetrazol-5- yl)imidazo[1,2-a]pyridin-8- yl)methoxy)-2- methoxyisonicotinaldehyde 126

ethyl 2-(5-(imidazo[1,2-a]pyridin- 8-ylmethoxy)-2-methoxypyridin- 4-yl)thiazolidine-4-carboxylate 127

2-methoxy-5-((2-(1-methyl-1H- pyrazol-4-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 128

5-((2-(1H-pyrazol-4-yl)pyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 129

2-methoxy-5-((2-(1-methyl-1H- pyrazol-5-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 130

2-methoxy-5-((2-(1-methyl-1H- pyrazol-3-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 131

5-((2-(2H-tetrazol-5-yl)pyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 132

2-methoxy-5-((2-(4-methyl-1H- pyrazol-5-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 133

5-((3-(1H-pyrazol-5- yl)isoquinolin-4-yl)methoxy)-2- methoxyisonicotinaldehyde 134

5-((2-(1H-pyrazol-1-yl)pyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 135

3-((2-(1H-pyrazol-1-yl)pyridin-3- yl)methoxy)-6- methylpicolinaldehyde 136

6-methyl-3-(pyridin-3- ylmethoxy)picolinaldehyde 137

methyl 8-(((4-formyl-6- methoxypyridin-3- yl)oxy)methyl)imidazo[1,2- a]pyridine-6-carboxylate 138

methyl 2-bromo-8-(((4-formyl-6- methoxypyridin-3- yl)oxy)methyl)imidazo[1,2- a]pyridine-6-carboxylate 139

3-(imidazo[1,5-a]pyridin-8- ylmethoxy)-6- methylpicolinaldehyde 140

5-(imidazo[1,5-a]pyridin-8- ylmethoxy)-2- methoxyisonicotinaldehyde 141

(5-(methoxycarbonyl)pyridin-3- yl)methyl 5-(((4-formyl-6- methoxypyridin-3- yl)oxy)methyl)nicotinate 142

5-((2-(1,4-dimethyl-1H-pyrazol-5- yl)pyridin-3-yl)methoxy)-2- methoxyisonicotinaldehyde 143

5-((2-(1,5-dimethyl-1H-pyrazol-4- yl)pyridin-3-yl)methoxy)-2- methoxyisonicotinaldehyde 144

2-hydroxyethyl 5-(((4-(1,3- dioxolan-2-yl)-6-methoxypyridin- 3-yl)oxy)methyl)nicotinate 145

methyl 5-(((4-(1,3-dioxolan-2-yl)- 6-methoxypyridin-3- yl)oxy)methyl)nicotinate 146

methyl 5-(((4-(bis(2- hydroxyethoxy)methyl)-6- methoxypyridin-3- yl)oxy)methyl)nicotinate 147

5-((2-(1,3-dimethyl-1H-pyrazol-4- yl)pyridin-3-yl)methoxy)-2- methoxyisonicotinaldehyde 148

5-((2-(1,3-dimethyl-1H-pyrazol-5- yl)pyridin-3-yl)methoxy)-2- methoxyisonicotinaldehyde 149

5-((2-(1-ethyl-1H-pyrazol-5- yl)pyridin-3-yl)methoxy)-2- methoxyisonicotinaldehyde 150

5-((2-(1-isopropyl-1H-pyrazol-5- yl)pyridin-3-yl)methoxy)-2- methoxyisonicotinaldehyde 151

2-methoxy-5-((2-(3-methyl-1H- pyrazol-1-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 152

5-(((4-(1,3-dioxolan-2-yl)-6- methoxypyridin-3- yl)oxy)methyl)nicotinic acid 153

(E)-2-methoxy-5-((2-(4-methyl- 1H-pyrazol-5-yl)pyridin-3- yl)methoxy)isonicotinaldehyde oxime 154

(E)-2-methoxy-5-(pyridin-3- ylmethoxy)isonicotinaldehyde oxime 155

2-(5-(imidazo[1,2-a]pyridin-8- ylmethoxy)-2-methoxypyridin-4- yl)thiazolidine 156

1-(2-(5-(imidazo[1,2-a]pyridin-8- ylmethoxy)-2-methoxypyridin-4- yl)thiazolidin-3-yl)ethanone 157

5-((2-(4-(1H-pyrazol-3- yl)piperazin-1-yl)pyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 158

2-(difluoromethoxy)-5- (imidazo[1,2-a]pyridin-8- ylmethoxy)isonicotinaldehyde 159

2-methoxy-5-((2-phenylpyridin-3- yl)methoxy)isonicotinaldehyde 160

5-((3-(1-isopropyl-1H-pyrazol-5- yl)pyridin-4-yl)methoxy)-2- methoxyisonicotinaldehyde 161

5-([2,3′-bipyridin]-3-ylmethoxy)- 2-methoxyisonicotinaldehyde 162

2-methoxy-5-((2-(o-tolyl)pyridin- 3-yl)methoxy)isonicotinaldehyde 163

2-methoxy-5-((2′-methoxy-[2,3′- bipyridin]-3- yl)methoxy)isonicotinaldehyde 164

methyl 4-(((2-formylpyridin-3- yl)oxy)methyl)benzoate 165

4-(((2-formyl-6-methylpyridin-3- yl)oxy)methyl)benzoic acid 166

4-(((2-formylpyridin-3- yl)oxy)methyl)benzoic acid 167

methyl 3-(((4-formylpyridin-3- yl)oxy)methyl)benzoate 168

methyl 3-(((2-formyl-6- methylpyridin-3- yl)oxy)methyl)benzoate 169

3-(((4-formylpyridin-3- yl)oxy)methyl)benzoic acid 170

3-(((2-formyl-6-methylpyridin-3- yl)oxy)methyl)benzoic acid 171

3-(((2-formylpyridin-3- yl)oxy)methyl)benzoic acid 172

2-methoxy-5-((2-(1-(2- methoxyethyl)-1H-pyrazol-5- yl)pyridin-3- yl)methoxy)isonicotinaldehyde 173

2-methoxy-5-((2-(1-propyl-1H- pyrazol-5-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 174

2-methoxy-5-((2-(1-(2,2,2- trifluoroethyl)-1H-pyrazol-5- yl)pyridin-3- yl)methoxy)isonicotinaldehyde 175

5-((2-(1-(2,2-difluoroethyl)-1H- pyrazol-5-yl)pyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 176

3-((2-(1-isopropyl-1H-pyrazol-5- yl)pyridin-3- yl)methoxy)picolinaldehyde 177

3-((2-(1-isopropyl-1H-pyrazol-5- yl)pyridin-3-yl)methoxy)-6- methylpicolinaldehyde 178

2-(difluoromethoxy)-5-((2-(1- isopropyl-1H-pyrazol-5- yl)pyridin-3- yl)methoxy)isonicotinaldehyde 179

5-(imidazo[1,2-a]pyridin-8- ylmethoxy)-2-(2- methoxyethoxy)isonicotinaldehyde 180

5-((2-(1-isopropyl-1H-pyrazol-5- yl)pyridin-3-yl)methoxy)-2-(2- methoxyethoxy)isonicotinaldehyde 181

5-((3-(1-isopropyl-1H-pyrazol-5- yl)pyrazin-2-yl)methoxy)-2- methoxyisonicotinaldehyde 182

3-((4-formyl-6-methoxypyridin-3- yloxy)methyl)picolinate 183

5-((2-(2-hydroxypropan-2- yl)pyridin-3-yl)methoxy)-2- methoxyisonicotinaldehyde 184

2-(2-methoxyethoxy)-5-((2-(1- methyl-1H-pyrazol-5-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 185

2-(2-methoxyethoxy)-5-((2-(1- methyl-1H-pyrazol-5-yl)pyridin-3- yl)methoxy)nicotinaldehyde 186

3-hydroxy-5-((2-(1-isopropyl-1H- pyrazol-5-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 187

3-(benzyloxy)-5- hydroxyisonicotinaldehyde 188

3-((2-(1-isopropyl-1H-pyrazol-5- yl)pyridin-3-yl)methoxy)-5- methoxyisonicotinaldehyde 189

5-((2-(2-isopropyl-2H-1,2,4- triazol-3-yl)pyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 190

5-((2-(1-isopropyl-4-methyl-1H- pyrazol-5-yl)pyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 191

5-((2-(1-(2-hydroxyethyl)-1H- pyrazol-5-yl)pyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 192

2,2,2-trifluoroacetic acid:6-(((4- formylpyridin-3- yl)oxy)methyl)picolinic acid (1:1) 193

2-methoxy-5-((2-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H- pyrazol-5-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 194

5-((2-(4-methyl-1H-pyrazol-5- yl)pyridin-3-yl)methoxy)-2-oxo- 1,2-dihydropyridine-4- carbaldehyde 195

5-((2-(1-cyclobutyl-1H-pyrazol-5- yl)pyridin-3-yl)methoxy)-2- methoxyisonicotinaldehyde 196

5-((2-(1-cyclohexyl-1H-pyrazol-5- yl)pyridin-3-yl)methoxy)-2- methoxyisonicotinaldehyde 197

5-((2-(1-(cyclohexylmethyl)-1H- pyrazol-5-yl)pyridin-3- yl)methoxy)-2- methoxyisonicotinaldehyde 198

5-((2-(1-cyclopentyl-1H-pyrazol- 5-yl)pyridin-3-yl)methoxy)-2- methoxyisonicotinaldehyde 199

2-(5-(3-((4-formyl-6- methoxypyridin-3- yloxy)methyl)pyridin-2-yl)-1H- pyrazol-1-yl)acetic acid 200

methyl 3-(5-(3-(((4-formyl-6- methoxypyridin-3- yl)oxy)methyl)pyridin-2-yl)-1H- pyrazol-1-yl)propanoate 201

3-(3-(3-((4-formyl-6- methoxypyridin-3- yloxy)methyl)pyridin-2-yl)-1H- pyrazol-1-yl)propanoic acid 202

3-(5-(3-(((4-formyl-6- methoxypyridin-3- yl)oxy)methyl)pyridin-2-yl)-1H- pyrazol-1-yl)propanoic acid 203

3-(((4-formyl-6-methoxypyridin-3- yl)oxy)methyl)benzoic acid 204

6-(((4-formylpyridin-3- yl)oxy)methyl)nicotinonitrile 2,2,2-trifluoroacetate 205

6-(((4-formylpyridin-3- yl)oxy)methyl)nicotinic acid hydrochloride 206

2,2,2-trifluoroacetic acid:6-(((4- formylpyridin-3-yl)oxy)methyl)- N-(methylsulfonyl)nicotinamide (2:1) 207

2-(2-methoxyethoxy)-5-((2-(1- (2,2,2-trifluoroethyl)-1H-pyrazol- 5-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 208

2-methoxy-5-((2-(1-(3,3,3- trifluoropropyl)-1H-pyrazol-5- yl)pyridin-3- yl)methoxy)isonicotinaldehyde 209

2-(2-methoxyethoxy)-5-((2-(1- (3,3,3-trifluoropropyl)-1H- pyrazol-5-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 210

2-methyl-5-((2-(1-(2,2,2- trifluoroethyl)-1H-pyrazol-5- yl)pyridin-3- yl)methoxy)isonicotinaldehyde 211

2-methyl-5-((2-(1-(3,3,3- trifluoropropyl)-1H-pyrazol-5- yl)pyridin-3- yl)methoxy)isonicotinaldehyde 212

3-((2-(1-(2,2,2-trifluoroethyl)-1H- pyrazol-5-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 213

3-((2-(1-(3,3,3-trifluoropropyl)- 1H-pyrazol-5-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 214

3-chloro-5-((2-(1-isopropyl-1H- pyrazol-5-yl)pyridin-3- yl)methoxy)isonicotinaldehyde 215

3-((2-(1-isopropyl-1H-pyrazol-5- yl)pyridin-3-yl)methoxy)-5- methylisonicotinaldehyde 216

3-chloro-5-((2-(1-(3,3,3- trifluoropropyl)-1H-pyrazol-5- yl)pyridin-3- yl)methoxy)isonicotinaldehyde 217

3-methyl-5-((2-(1-(2,2,2- trifluoroethyl)-1H-pyrazol-5- yl)pyridin-3- yl)methoxy)isonicotinaldehyde

In one group of embodiments, the compound is selected from 5-hydroxy-2-(2-methoxyethoxy)isonicotinaldehyde (Compound 218), 5-hydroxy-2-(2-methoxyethoxy)nicotinaldehyde (Compound 219), 5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-oxo-1,2-dihydropyridine-4-carbaldehyde (Compound 220), 5-((2-(4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-oxo-1,2-dihydropyridine-4-carbaldehyde (Compound 221), or a tautomer or pharmaceutically acceptable salt thereof.

In one group of embodiments, the compound is selected from:

-   5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-methoxyisonicotinaldehyde, -   2-methoxy-5-((5-methylpyridin-3-yl)methoxy)isonicotinaldehyde, -   5-(isoquinolin-1-ylmethoxy)-2-methoxyisonicotinaldehyde, -   2-methoxy-5-(quinolin-2-yl)methoxy)isonicotinaldehyde, -   2-methoxy-5-(pyridin-4-ylmethoxy)isonicotinaldehyde, -   3-(imidazo[1,2-a]pyridin-8-ylmethoxy)-6-methylpicolinaldehyde, -   methyl     2-((4-formyl-6-methoxypyridin-3-yloxy)methyl)imidazo[1,2-a]pyridine-8-carboxylate, -   2-methoxy-5-((3-methyl-[1,2,4]triazolo[4,3-a]pyridin-8-yl)methoxy)isonicotinaldehyde, -   5-((2-bromopyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde, -   5-((2-(1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-hydroxyisonicotinaldehyde, -   5-((5-bromopyridin-3-yl)methoxy)-2-hydroxyisonicotinaldehyde, -   2-methoxy-5-((5-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinic acid, -   2-methoxy-5-(quinolin-3-ylmethoxy)isonicotinaldehyde, -   2-methoxy-5-((1-methyl-1H-indazol-4-yl)methoxy)isonicotinaldehyde, -   tert-butyl     4-((2-formyl-6-methylpyridin-3-yloxy)methyl)-1H-indazole-1-carboxylate, -   6-methyl-3-((1-methyl-1H-indazol-6-yl)methoxy)picolinaldehyde, -   6-methyl-3-((1-methyl-1H-indazol-7-yl)methoxy)picolinaldehyde, -   3-(isoquinolin-1-ylmethoxy)-6-methylpicolinaldehyde. -   5-(benzo[d]oxazol-4-ylmethoxy)-2-methoxyisonicotinaldehyde, -   3-((1,5-naphthyridin-4-yl)methoxy)-6-methylpicolinaldehyde, -   6-methyl-3-((1-methyl-1H-indazol-5-yl)methoxy)picolinaldehyde, -   6-methyl-3-(quinolin-5-ylmethoxy)picolinaldehyde, -   2-methoxy-5-(quinolin-5-ylmethoxy)isonicotinaldehyde, -   2-methoxy-5-((2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   2-methoxy-5-((2-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   5-((2-(2H-tetrazol-5-yl)pyridin-3-yl)methoxy)-2-hydroxyisonicotinaldehyde, -   2-methoxy-5-((2-(4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   5-((3-(1H-pyrazol-5-yl)isoquinolin-4-yl)methoxy)-2-hydroxyisonicotinaldehyde, -   5-((2-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-2-hydroxyisonicotinaldehyde, -   5-(imidazo[1,5-a]pyridin-8-ylmethoxy)-2-methoxyisonicotinaldehyde, -   5-((2-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methoxy)-2-hydroxyisonicotinaldehyde, -   5-((2-(1-ethyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-hydroxyisonicotinaldehyde, -   5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-hydroxyisonicotinaldehyde, -   2-(difluoromethoxy)-5-(imidazo[1,2-a]pyridin-8-ylmethoxy)isonicotinaldehyde, -   2-methoxy-5-((2-phenylpyridin-3-yl)methoxy)isonicotinaldehyde, -   5-((3-(1-isopropyl-1H-pyrazol-5-yl)pyridin-4-yl)methoxy)-2-hydroxyisonicotinaldehyde, -   5-([2,3′-bipyridin]-3-ylmethoxy)-2-methoxyisonicotinaldehyde, -   2-methoxy-5-((2-(o-tolyl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   2-methoxy-5-((2′-methoxy-[2,3′-bipyridin]-3-yl)methoxy)isonicotinaldehyde, -   4-(((2-formyl-6-methylpyridin-3-yl)oxy)methyl)benzoic acid, -   4-(((2-formylpyridin-3-yl)oxy)methyl)benzoic acid, -   methyl 3-(((4-formylpyridin-3-yl)oxy)methyl)benzoate, -   methyl 3-(((2-formyl-6-methylpyridin-3-yl)oxy)methyl)benzoate, -   3-(((4-formylpyridin-3-yl)oxy)methyl)benzoic acid, -   3-(((2-formyl-6-methylpyridin-3-yl)oxy)methyl)benzoic acid, -   3-(((2-formylpyridin-3-yl)oxy)methyl)benzoic acid, -   2-methoxy-5-((2-(1-(2-methoxyethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   2-methoxy-5-((2-(1-propyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   2-methoxy-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   5-((2-(1-(2,2-difluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde, -   3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)picolinaldehyde, -   3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-6-methylpicolinaldehyde, -   2-(difluoromethoxy)-5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-(2-methoxyethoxy)isonicotinaldehyde, -   5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-(2-methoxyethoxy)isonicotinaldehyde, -   5-((3-(1-isopropyl-1H-pyrazol-5-yl)pyrazin-2-yl)methoxy)-2-hydroxyisonicotinaldehyde, -   3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)picolinate, -   5-((2-(2-hydroxypropan-2-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde, -   2-(2-methoxyethoxy)-5-((2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   2-(2-methoxyethoxy)-5-((2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)nicotinaldehyde, -   3-hydroxy-5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde. -   3-(benzyloxy)-5-hydroxyisonicotinaldehyde, -   3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-5-hydroxyisonicotinaldehyde, -   5-((2-(2-isopropyl-2H-1,2,4-triazol-3-yl)pyridin-3-yl)methoxy)-2-hydroxyisonicotinaldehyde, -   5-((2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-hydroxyisonicotinaldehyde, -   5-((2-(1-(2-hydroxyethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-hydroxyisonicotinaldehyde, -   6-(((4-formylpyridin-3-yl)oxy)methyl)picolinic acid, -   2,2,2-trifluoroacetic     acid:6-(((4-formylpyridin-3-yl)oxy)methyl)picolinic acid (1:1), -   2-methoxy-5-((2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   5-((2-(4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-oxo-1,2-dihydropyridine-4-carbaldehyde, -   5-((2-(1-cyclobutyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde, -   5-((2-(1-cyclohexyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde, -   5-((2-(1-(cyclohexylmethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde, -   5-((2-(1-cyclopentyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde, -   2-(5-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetic     acid, -   methyl     3-(5-(3-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate, -   3-(3-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoic     acid, -   3-(5-(3-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoic     acid, -   3-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)benzoic acid, -   6-(((4-formylpyridin-3-yl)oxy)methyl)nicotinonitrile     2,2,2-trifluoroacetate, -   6-(((4-formylpyridin-3-yl)oxy)methyl)nicotinic acid, -   6-(((4-formylpyridin-3-yl)oxy)methyl)nicotinic acid hydrochloride, -   6-(((4-formylpyridin-3-yl)oxy)methyl)-N-(methylsulfonyl)nicotinamide, -   2,2,2-trifluoroacetic     acid:6-(((4-formylpyridin-3-yl)oxy)methyl)-N-(methylsulfonyl)nicotinamide     (2:1),     2-(2-methoxyethoxy)-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   2-methoxy-5-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   2-(2-methoxyethoxy)-5-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   2-methyl-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   2-methyl-5-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   3-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   3-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   3-chloro-5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, -   3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-5-methylisonicotinaldehyde, -   3-chloro-5-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,     and -   3-methyl-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,     or a tautomer or pharmaceutically acceptable salt thereof.

In one group of embodiments, provided is a pharmaceutical composition comprising a compound of any of the above embodiments or a tautomer or pharmaceutically acceptable salt thereof.

In one group of embodiments, provided is a compound in any of the Examples or Tables. In another group of embodiments, provided are any combinations of subembodiments as disclosed herein including any combination of elements disclosed herein including the a selection of any single elements.

The compounds of the present invention may be prepared by known organic synthesis techniques, including the methods described in more detail in the Examples.

In one group of embodiments, provided is an intermediate compound used in the preparation of the compounds disclosed herein.

In one group of embodiments, provided are methods for preparing the compounds disclosed herein.

For example, Scheme I shows a synthetic route for the synthesis of the compounds of Formula (I) where X is O and Y is CH₂. Phenol 1.1 is contacted with intermediate 1.2 in the presence of base under ether forming conditions to give ether 1.3, where Lg represents a leaving group such as a halogen leaving group. Conversely, when X is O and Y is CH₂, the compounds of Formula (I) can be prepared using the appropriate starting materials where the OH moiety of intermediate 1.1 is replaced with a leaving group and the Lg group of intermediate 1.2 is replaced with an OH group.

Scheme II shows an example of a synthetic route for the synthesis of the compounds of Formula (I) where X and Y are CH₂. Alkene 2.1 is contacted with alkene 2.2 under metathesis forming conditions in the presence of an appropriate transition metal catalyst. Suitable catalysts include ruthenium catalysts such as Grubbs' catalyst. Product 2.3 is then hydrogenated to give compound 2.4.

Scheme III shows an example of a synthetic route for the synthesis of the compounds of Formula (I) where R⁶ together with R^(1b) form a cyclic ether. Compound 3.1, is reacted with diethylphosphite and a base such as sodium methoxide to give intermediate 3.2, that is then condensed with aldehyde 33 to give alkene 3.4. Treatment of the alkene with H₂ under hydrogenation conditions gives lactone 3.4, which is then reduced with a suitable reducing agent such as LiBHEt₃ to give cyclic hemiacetal 3.5.

Scheme IV shows an example of synthesis of the compounds of Formula (I) where Q is pyridine-3-yl and R^(a) heteroaryl. Acid 4.1 is reduced to alcohol 4.2 using known methods such as by forming the anhydride (e.g. treatment with triethylamine and i-butyl chloroformate) followed by reduction with NaBH₄. Alcohol 4.2 is converted to chloride 4.3 such as by treatment with thionyl chloride. Coupling of the halide with alcohol 4.4 under ether forming conditions gives the precursor 4.5 that can be functionalized with a variety to heteroaryl R^(a) groups. For example, 4.5 can be coupled with pyrazole 4.6 under known organometallic coupling conditions (e.g. Pd(PPh₃)₄) to give 4.7, where PG is a nitrogen protecting group such as a silyl protecting group that can be removed to give the product 4.8.

One skilled in the art will recognize that in certain embodiments it may be advantageous to use a protecting group strategy. The protecting group can be removed using methods known to those skilled in the art.

The compounds of the present invention may generally be utilized as the free base. Alternatively, the compounds of this invention may be used in the form of acid addition salts.

It is understood that in another group of embodiments, any of the above embodiments may also be combined with other embodiments listed herein, to form other embodiments of the invention. Similarly, it is understood that in other embodiments, listing of groups includes embodiments wherein one or more of the elements of those groups is not included.

III. Compositions and Methods of Administration

Depending on the intended mode of administration, the pharmaceutical compositions may be in the form of solid, semi-solid or liquid dosage forms, preferably in unit dosage form suitable for single administration of a precise dosage. In addition to an effective amount of the active compound(s), the compositions may contain suitable pharmaceutically-acceptable excipients, including adjuvants which facilitate processing of the active compounds into preparations which can be used pharmaceutically. “Pharmaceutically acceptable excipient” refers to an excipient or mixture of excipients which does not interfere with the effectiveness of the biological activity of the active compound(s) and which is not toxic or otherwise undesirable to the subject to which it is administered.

For solid compositions, conventional excipients include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmacologically administrable compositions can, for example, be prepared by dissolving, dispersing, etc., an active compound as described herein and optional pharmaceutical adjuvants in water or an aqueous excipient, such as, for example, water, saline, aqueous dextrose, and the like, to form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary excipients such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc.

For oral administration, the composition will generally take the form of a tablet or capsule, or it may be an aqueous or nonaqueous solution, suspension or syrup. Tablets and capsules are preferred oral administration forms. Tablets and capsules for oral use will generally include one or more commonly used excipients such as lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. When liquid suspensions are used, the active agent may be combined with emulsifying and suspending excipients. If desired, flavoring, coloring and/or sweetening agents may be added as well. Other optional excipients for incorporation into an oral formulation include preservatives, suspending agents, thickening agents, and the like.

Injectable formulations can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solubilization or suspension in liquid prior to injection, or as emulsions or liposomal formulations. The sterile injectable formulation may also be a sterile injectable solution or a suspension in a nontoxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media.

The pharmaceutical compositions of this invention may also be formulated in lyophilized form for parenteral administration. Lyophilized formulations may be reconstituted by addition of water or other aqueous medium and then further diluted with a suitable diluent prior to use. The liquid formulation is generally a buffered, isotonic, aqueous solution. Examples of suitable diluents are isotonic saline solution, 5% dextrose in water, and buffered sodium or ammonium acetate solution. Pharmaceutically acceptable solid or liquid excipients may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.

Typically, a pharmaceutical composition of the present invention is packaged in a container with a label, or instructions, or both, indicating use of the pharmaceutical composition in the treatment of of the indicated disease.

The pharmaceutical composition may additionally contain one or more other pharmacologically active agents in addition to a compound of this invention.

Dosage forms containing effective amounts of the modulators are within the bounds of routine experimentation and within the scope of the invention. A therapeutically effective dose may vary depending upon the route of administration and dosage form. The representative compound or compounds of the invention is a formulation that exhibits a high therapeutic index. The therapeutic index is the dose ratio between toxic and therapeutic effects which can be expressed as the ratio between LD₅₀ and ED₅₀. The LD₅₀ is the dose lethal to 50% of the population and the ED₅₀ is the dose therapeutically effective in 50% of the population. The LD₅₀ and ED₅₀ are determined by standard pharmaceutical procedures in animal cell cultures or experimental animals. It should be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex and diet of the patient, and the time of administration, rate of excretion, drug combination, judgment of the treating physician and severity of the particular disease being treated. The amount of active ingredient(s) will also depend upon the particular compound and other therapeutic agent, if present, in the composition.

IV. Methods

In one group of embodiments, provided is a method for increasing tissue oxygenation, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of the above embodiments or a tautomer or pharmaceutically acceptable salt thereof.

In one group of embodiments, provided is a method for treating a condition associated with oxygen deficiency, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of the above embodiments or a tautomer or pharmaceutically acceptable salt thereof.

In one group of embodiments, provided is a method for treating sickle cell disease, cancer, a pulmonary disorder, stroke, high altitude sickness, an ulcer, a pressure sore, Alzheimer's disease, acute respiratory disease syndrome, and a wound, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of the above embodiments or a tautomer or pharmaceutically acceptable salt thereof.

In one group of embodiments, provided is a method for increasing tissue oxygenation or for treating a condition associated with oxygen deficiency, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound Formula (II):

or a tautomer or pharmaceutically acceptable salt thereof,

wherein Q is selected from the group consisting of aryl, heteroaryl, and heterocycloalkyl, each optionally substituted with one to three R^(a);

Y is O or CR^(1a)R^(1b), where R^(1a) is H or halo and R^(1b) is selected from the group consisting of H, halo, and OH;

X is selected from the group consisting of O, >CH(CH₂)_(n)R⁸, and C(R⁹)₂ where n is 0 or 1, R⁸ is OH, and R⁹ is independently H or halo; or Y—X taken together is —NHC(O)— or —C(O)NH—;

R², R³, R⁴, and R⁵ are independently absent or selected from the group consisting of hydrogen, halo, R^(b), OR^(d), O(CH₂)_(z)OR^(d), O(CH₂)_(z)NR^(d)R^(d), OC(O)R^(e), SR^(d), CN, NO₂, CO₂R^(d), CONR^(d)R^(d), C(O)R^(d), OC(O)NR^(d)R^(d), NR^(d)R^(d), NR^(d)C(O)R^(e), NR^(d)C(O)₂R^(e), NR^(d)C(O)NR^(d)R^(d), S(O)R^(e), S(O)₂R^(e), NR^(d)S(O)₂R^(e), S(O)₂NR^(d)R^(d), and N₃ where z is 0, 1, 2, or 3; or R⁵ is —(CH₂)_(p)R^(5a) where p is 0 or 1 and R^(5a) is OH;

R⁶ and R⁷ together form oxo or an aldehyde protecting group, or R⁶ together with R^(1b), R⁸, or R⁵ forms a cyclic ether where one of R^(1b), R⁸, or R^(5a) is O, R⁶ is a bond, and R⁷ is selected from the group consisting of OH, C₁₋₈alkoxy, and haloC₁₋₈alkoxy;

T¹, T², T³, and T⁴ are independently C or N provided that at least one of T¹, T², T³, and T⁴ is N and at least one of T¹, T², T³, and T⁴ is C;

each R⁸ is independently selected from the group consisting of halo, R^(b), OR^(d), O(CH₂)_(u)OR^(d), O(CH₂)_(u)NR^(d)R^(d), O(CH₂)_(u)NR^(d)C(O)R^(e), O(CH₂)_(u)NR^(d)C(O)₂R^(e), O(CH₂)_(u)NR^(d)S(O)₂R^(e), NH₂, —(CH₂)_(k)OC(O)R^(e), —(CH₂)_(k)SR^(d), CN, NO₂, —(CH₂)_(k)CO₂(C₁₋₈alkyl)OH, —(CH₂)_(k)CO₂(C₁₋₈alkyl)(heteroaryl)C(O)(C₁₋₈alkyl), —(CH₂)_(k)CO₂R^(d), —(CH₂CONR^(d)R^(d), —(CH₂)_(k)NR^(d)C(O)R^(e), —(CH₂)_(k)NR^(d)C(O)₂R^(e), —(CH₂)_(k)C(O)R^(d), —(CH₂)_(k)OC(O)NR^(d)R^(d), —NR^(d)(CH₂)_(u)OR^(d), —NR^(d)(CH₂)_(u)NR^(d)R^(d), —NR^(d)(CH₂)_(u)NR^(d)C(O)R^(c), —NR^(d)(CH₂)_(u)NR^(d)C(O)₂R^(e), —NR^(d)(CH₂)_(u)NR^(d)S(O)₂R^(e), —(CH₂)_(k)NR^(d)C(O)R^(e), —(CH₂)_(k)NR^(d)C(O)₂R^(d), —(CH₂)_(k)NR^(d)C(O)NR^(d)R^(d), —(CH₂)_(k)S(O)R^(e), —(CH₂)_(k)S(O)₂R^(e), —(CH₂)_(k)NR^(d)S(O)₂R^(e), —C(O)(CH₂)_(k)NR^(d)S(O)₂R^(e), —(CH₂)_(k)C(O)NR^(d)S(O)₂R^(e), —(CH₂)_(k)S(O)₂NR^(d)R^(d), N₃, —(CH₂)_(k)aryl optionally substituted with one to three R^(c), —NR^(d)(CH₂)_(k)aryl optionally substituted with one to three R^(c), —(CH₂)_(k)heteroaryl optionally substituted with one to three R^(c), —NR^(d)(CH₂)heteroaryl optionally substituted with one to three R^(c), —(CH₂)_(k)heterocycloalkyl optionally substituted with one to three R^(c), and —NR^(d)(CH₂)_(k)heterocycloalkyl optionally substituted with one to three R^(c) where k is 0, 1, 2, 3, 4, 5, or 6 and u is 1, 2, 3, 4, 5, or 6;

each R^(b) is independently selected from the group consisting of C₁₋₈alkyl, C₂₋₈alkenyl, and C₂₋₈alkynyl, each optionally independently substituted with one to three halo, OR^(d), or NR^(d)R^(d);

each R^(c) is independently selected from the group consisting of halo, C₁₋₈alkyl, haloC₁₋₈alkyl, C₂₋₈alkenyl, haloC₂₋₈alkenyl, C₂₋₈alkynyl, haloC₂₋₈alkynyl, (CH₂)_(m)OR^(f), OC(O)R^(g), SR^(f), CN, NO₂, (CH₂)_(m)CO₂R^(f), CONR^(f)R^(f), C(O)R^(f), OC(O)NR^(f)R^(f), (CH₂)_(m)NR^(f)R^(f), NR^(f)C(O)R^(g), NR^(f)C(O)₂R^(g), NR^(f)C(O)NR^(f)R^(f), S(O)R^(g), S(O)₂R^(g), NR^(f)S(O)₂R^(g), S(O)₂NR^(f)R^(f), N₃, (R^(f))_(m)SiC₁₋₈alkyl, heteroaryl optionally substituted with one to three R^(h), cycloalkyl optionally substituted with one to three R^(h), and heterocycloalkyl optionally substituted with one to three R^(h) where m is selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6;

each R^(h) is independently selected from the group consisting of halo, C₁₋₈alkyl, haloC₁₋₈alkyl, OR^(j), OC(O)R, SR^(j), NO₂, CO₂R^(j), CONR^(j)R^(j), C(O)R^(j), OC(O)NR^(j)R^(j), NR^(j)R^(j), NR^(j)C(O)R^(t), NR^(j)C(O)₂R^(t), NR^(j)C(O)NR^(j)R^(j), S(O)R^(t), S(O)₂R^(t), NR^(j)S(O)₂R^(t), and S(O)₂NR^(j)R^(j);

R^(d), R^(f), and R^(j) are each independently selected from the group consisting of hydrogen, C₁₋₈ alkyl, haloC₁₋₈alkyl, C₂₋₈ alkenyl, haloC₂₋₈alkenyl, C₂₋₈ alkynyl, and haloC₂₋₈alkynyl; and

R^(e), R^(g), and R^(t) are each independently selected from the group consisting of C₁₋₈alkyl, haloC₁₋₈alkyl, C₂₋₈ alkenyl, haloC₂₋₈alkenyl, C₂₋₈ alkynyl, and haloC₂₋₈alkynyl;

provided that X and Y are not both O;

provided that when X is O, R^(1b) is not OH; and

provided that when Y is O, and n is 0, R⁸ is not OH.

In one group of embodiments, provided is a method of any of the groups of embodiments disclosed herein, wherein at least one z is 0. In another group of embodiments, at least one z is 1. In yet another group of embodiments, at least one z is 2. In still another group of embodiments, at least one z is 3. In another group of embodiments, no z is 0.

V. Examples

The following examples are offered to illustrate, but not to limit, the claimed invention.

PREPARATIVE EXAMPLES

The starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, 1967-2004, Volumes 1-22; Rodd's Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals; and Organic Reactions, Wiley & Sons: New York, 2005, Volumes 1-65.

The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

Unless specified to the contrary, the reactions described herein preferably are conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range of from about −78° C. to about 150° C., more preferably from about 0° C. to about 125° C., and most preferably and conveniently at about room (or ambient) temperature, e.g., about 20° C. to about 75° C.

Referring to the examples that follow, compounds of the present invention were synthesized using the methods described herein, or other methods known in the art.

Example 1 Preparation of 3-(pyridin-3-ylmethoxy)isonicotinaldehyde

Step 1:

) Acetyl chloride (20 mL) was added dropwise to methanol (200 mL) at 0° C. After the addition, the reaction mixture was stirred at this temp for 15 min and then 4.0 g of the acid was added. The reaction mixture was heated at reflux for 12 h. Methanol was removed to give a residue, which was then carefully neutralized with aq. sat. NaHCO₃ and then extracted with EtOAc (3×). The organic layers were combined, dried and evaporated to give the ester as a yellow solid, which was used in the next step without further purification.

Step 2:

A mixture of chloride (300 mg, 1.5 mmol, 1.0 eq), hydroxypyridne (230 mg, 1.5 mmol, 1.0 eq) and potassium carbonate (621 mg, 4.5 mmol, 3.0 eq) were taken in DMF (10 mL) and the reaction mixture was heated at 80° C. for 4 h. Solvent was removed and the crude was purified by column chromatography (Hexane/EtOAc to EtOAc/MeOH) to provide the coupled product.

Step 3:

To an ice cold solution of ester (1.5 mmol, 1.0 eq) in THF (15 mL) was slowly added LAH solution (1.5 mL, 2M solution in THF) and the reaction mixture was stirred at this temp for 30 min. Then excess ethyl acetate was added slowly to quench excess LAH. Then water (1 mL), 15% NaOH (1 mL) and water (3 mL) were added and stirred at rt for 30 min. The clear solution was filtered and the solid was washed with ethyl acetate (3×). The organic layers were combined, dried and evaporated to give the crude alcohol, which was used in the next step without further purification.

Step 4:

To a solution of the above alcohol (1.5 mmol, 1.0 eq) in DCM (15 mL) was added Dess-Martin reagent (2.25 mmol, 454 mg, 1.5 eq) and the reaction mixture was stirred at rt for 1 h. Solution was diluted with 25 mL DCM and then a 1:1 mixture of sat. NaHCO₃ and sat. Na₂S₂O₃ was added and stirred for 30 min to get two clear layers. Aqueous layer was separated and washed with DCM (3×). Organic layer was dried and evaporated to give a crude product, which was purified by column chromatography (EtOAc/MeOH). NMR (400 MHz, CDCl₃): δ 5.35 (s, 2H), 7.49 (m, 1H), 7.60 (d, 1H), 8.02 (m, 1H), 8.25 (m, 1H), 8.38 (s, 1H), 8.53 (m, 1H), 8.70 (m, 1H) 10.58 (s, 1H); MS: exact mass calculated for C₁₂H₁₀N₂O₂, 214.07; m/z found, 215 [M+H]⁺.

Example 2 Preparation of 3-(imidazo[1,2-a]pyridin-8-ylmethoxy)isonicotinaldehyde

Step 1:

To a DMF (15 mL) solution of the chloride (300 mg, 1.5 mmol, 1.0 eq) and phenol (230 mg, 1.5 mmol, 1.0 eq) was added K₂CO₃ (621 mg, 4.5 mmol, 3.0 eq) and the reaction mixture was heated at 80-90° C. for 5 h. Solvent was removed and the residue was purified by column chromatography (EtOAc/MeOH) to give the alkylation product. MS: exact mass calculated for C₁₅H₁₃N₃O₃, 283.10; m/z found, 284 [M+H]⁺.

Step 2:

To a cooled solution of the ester (1.5 mmol, 1.0 eq) in THF (15 mL) was slowly added LAH in THF (1.5 mL, 2.0 M solution in THF, 2.0 eq) and the reaction mixture was stirred at this temperature for 30 min. Excess ethyl acetate was added very slowly followed by water (1.0 mL), 15% NaOH (1.0 mL) and water (3.0 mL) and the mixture was stirred at rt for 30 min. The solution was filtered and the solid was washed with ethyl acetate (3×). Combined organic layers were dried and evaporated to provide the alcohol, which was used in the next step without further purification. MS: exact mass calculated for C₁₄H₁₃N₃O₂, 255.10; m/z found, 256 [M+H]⁺.

Step 3:

To a solution of the above alcohol (1.5 mmol, 1.0 eq) in DCM (15 mL) was added Dess-Martin reagent (2.25 mmol, 954 mg, 1.5 eq) and the reaction mixture was stirred at rt for 1 h. The reaction was then diluted with 25 mL DCM and then a 1:1 mixture of sat. NaHCO₃ and sat. Na₂S₂O₃ was added and stirred for 30 min to get two clear layers. The aqueous layer was separated and washed with DCM (3×). The organic layer was dried and evaporated to give a crude product which was purified by column chromatography (EtOAc/MeOH). MS: exact mass calculated for C₁₄H₁₁N₃O₂, 253.09; m/z found, 254 [M+H]⁺.

Example 3 Preparation of 3-(imidazo[1,5-a]pyridin-8-ylmethoxy)isonicotinaldehyde

Step 1:

To a solution of chloride (200 mg, 1.0 mmol, 1.0 eq), and phenol (153 mg, 1.0 mmol, 1.0 eq) in DMF (15 mL) was added K₂CO₃ (414 mg, 3.0 mmol, 3.0 eq) and the reaction mixture was heated at 80-90° C. for 5 h. Solvent was removed and the residue was purified by column chromatography (EtOAc/MeOH) to give the alkylation product. MS: exact mass calculated for C₁₅H₁₃N₃O₃, 283.10; m/z found, 284 [M+H]⁺.

Step 2:

To a cooled solution of the ester (1.0 mmol, 1.0 eq) in THF (15 mL) was slowly added LAH in THF (4 mmol, 2.0 mL, 2.0 M solution in THF, 4.0 eq) and the reaction mixture was stirred at this temperature for 30 min. Excess ethyl acetate was added very slowly followed by water (1.0 mL), 15% NaOH (1.0 mL) and water (3.0 mL) and the mixture was stirred at rt for 30 min. Filtered and the solid was washed with ethyl acetate (3×). Combined organic layers were dried and evaporated to provide the alcohol, which was used in the next step without further purification. MS: exact mass calculated for C₁₄H₁₃N₃O₂, 255.10; m/z found, 286 [M+H]⁺.

Step 3:

To a cooled solution of the ester (1.0 mmol, 1.0 eq) in THF (15 mL) was slowly added LAH in THF (4 mmol, 2.0 mL, 2.0 M solution in THF, 4.0 eq) and the reaction mixture was stirred at this temperature for 30 min. Excess ethyl acetate was added very slowly followed by water (1.0 mL), 15% NaOH (1.0 mL) and water (3.0 mL) and the mixture was stirred at rt for 30 min. Reaction was filtered and the solid was washed with ethyl acetate (3×). Combined organic layers were dried and evaporated to provide the alcohol, which was used in the next step without further purification. MS: exact mass calculated for C₁₄H₁₃N₃O₂, 255.10; m/z found, 286 [M+H]⁺.

Example 4 Preparation of 4-(pyridin-3-ylmethoxy)nicotinaldehyde

4-chloro-3-pyridine aldehyde (1.0 g, 7 mmol, 1.0 eq), 3-hydroxymethyl pyridine (5.4 g, 49.45 mmol, 7 eq) and p-tolunesulfonic acid mon hydrate (1.3 g, 7.0 mmol, 1.0 eq) in benzene (30 mL) were heated using a Dean-Stark trap for 24 h. Solvent was removed and purified by column chromatography to provide the alkylation product. MS: exact mass calculated for C₁₂H₁₀N₂O₂, 214.22; m/z found, 215 [M+H]⁺.

Example 5 Preparation of 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-hydroxyisonicotinaldehyde (Compound 5)

Step 1:

To a mixture of 6-methoxypyridin-3-ol (25 g, 0.2 mol) and K₂CO₃ (82.8 g, 0.6 mol) in DMF (250 mL) was added bromomethyl methyl ether (30 g, 0.24 mmol) slowly at rt for a period of 1 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified on silica gel with 25% EtOAc/hexanes as eluent to give 2-methoxy-5-(methoxymethoxy)pyridine (20 g, 59%) as a colorless oil. LRMS (M+H⁺) m/z 170.1

Step 2:

To a solution of 2-methoxy-5-(methoxymethoxy)pyridine (20 g, 0.12 mol) in THF was added diisopropylamine (0.24 g, 2.4 mmol). The solution was cooled to −40° C. followed by addition of MeLi (3M/THF, 72 mL, 0.216 mol) slowly. The resulting mixture was warmed to 0° C., stirred at 0° C. for 3 h, cooled back down to −40° C. and added N-formylpiperidine (24 mL, 0.216 mol). After stirring at −40° C. for 2 h, the mixture was quenched with a mixed solution of HCl (37%, 120 mL) and THF (250 mL). The temperature was then raised to rt and diluted with water (200 mL) and EtOAc (200 mL). The pH of the mixture was adjusted to 8-9 with solid K₂CO₃ and extracted with EtOAc (300 mL) twice. The organic layer was combined, dried over Na₂SO₄, and concentrated. The residue was purified on silica gel with 25% EtOAc/hexanes as eluent to give 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (10 g, 42%) as a pale yellow oil. ¹H NMR (400 MHz; CD₃OD) 7.90 (s, 1 H), 6.92 (s, 1 H), 5.64 (s, 1 H), 5.20 (s, 2 H), 3.84 (s, 3 H), 3.48 (s, 3 H).

Step 3:

To a solution of 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (10 g, 0.05 mol) in THF (100 mL) was added 3 N HCl (150 mL). The reaction was stirred at 50° C. for 30 min, cooled to rt, and diluted with water (100 mL). The mixture was neutralized to pH 7-8 and extracted with EtOAc (200 mL) three times. The organic layer was dried over Na₂SO₄ and concentrated to give 5-hydroxy-2-methoxyisonicotinaldehyde (4.2 g, 55%) as a yellow solid. ¹H NMR (400 MHz; DMSO) δ=10.31 (s, 1 H), 8.03 (s, 1 H), 6.89 (s, 1 H), 3.80 (s, 3 H).

Step 4:

A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (723.6 mg, 4.7 mmol), 8-(chloromethyl)-imidazol[1,2-a]pyridine (785 mg, 4.7 mmol), and K₂CO₃ (1.9 g, 14.1 mmol) in DMF (20 mL) was heated at microwave reactor at 125° C. for 15 min. The mixture was filtered and concentrated. The residue was purified on silica gel (50-100% EtOAc in hexanes) to give 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-methoxyisonicotinaldehyde (500 mg, 38%) as an off-white solid. ¹H NMR (400 MHz; DMSO) δ=10.37 (s, 1 H), 8.58 (d, 1 H), 8.39 (s, 1 H), 8.02 (s, 1H), 7.61 (s, 1 H), 7.44 (d, 1 H), 6.98 (s, 1 H), 6.93 (t, 1 H), 5.61 (s, 2 H), 3.84 (s, 3 H). LRMS (M+H⁺) m/z 284.0.

Examples 6-13 were synthesized according to Example 5.

Example 6 Preparation of 2-methoxy-5-((5-methylpyridin-3-yl)methoxy)isonicotinaldehyde (Compound 43)

¹H NMR (400 MHz, CDCl3) δ 10.43 (s, 1H), 8.69 (s, 1H), 8.56 (s, 1H), 8.09 (s, 1H), 7.94 (s, 1H), 7.15-7.09 (m, 1H), 5.29 (s, 2H), 3.94 (s, 3H), 2.51 (s, 3H). 1H NMR (400 MHz, CDCl3) δ 10.43 (s, 1H), 8.69 (s, 1H), 8.56 (s, 1H), 8.09 (s, 1H), 7.94 (s, 1H), 7.15-7.09 (m, 1H), 5.29 (s, 2H), 3.94 (s, 3H), 2.51 (s, 3H).

Example 7 Preparation of 5-(isoquinolin-1-ylmethoxy)-2-methoxyisonicotinaldehyde (Compound 44)

¹H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 8.54 (d, J=5.7 Hz, 1H), 8.30 (s, 1H), 8.31 (d, J=8.6 Hz, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.78-7.63 (m, 3H), 7.07 (d, J=0.5 Hz, 1H), 5.82 (s, 2H), 3.91 (s, 3H).

Example 8 Preparation of 2-methoxy-5-(quinolin-2-ylmethoxy)isonicotinaldehyde (Compound 45)

¹H NMR (400 MHz, CDCl3) δ 10.61 (s, 1H), 8.26 (d, J=8.5 Hz, 1H), 8.12 (s, 1H), 8.10 (d, J=8.5 Hz, 1H), 7.87 (dd, J=8.2, 1.1 Hz, 1H), 7.78 (ddd, J=8.4, 6.9, 1.4 Hz, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.60 (ddd, J=8.1, 7.0, 1.1 Hz, 1H), 7.13 (s, 1H), 5.52 (s, 2H), 3.91 (s, 3H).

Example 9 Preparation of 2-methoxy-5-(pyridin-4-ylmethoxy)isonicotinaldehyde (Compound 46)

¹H NMR (400 MHz, CDCl3) δ 10.44 (s, 1H), 8.59 (d, J=6.0 Hz, 2H), 7.92 (s, 1H), 7.30 (d, J=6.0 Hz, 2H), 7.06 (s, 1H), 5.16 (s, 2H), 3.84 (s, 3H).

Example 10 3-(imidazo[1,2-a]pyridin-8-ylmethoxy)-6-methylpicolinaldehyde (Compound 49)

¹H NMR (400 MHz, DMSO) δ 10.22 (s, 1H), 8.56 (d, J=6.7 Hz, 1H), 8.02 (s, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.60 (s, 1H), 7.53 (d, J=8.7 Hz, 1H), 7.47 (d, J=6.7 Hz, 1H), 6.96 (t, J=6.9 Hz, 1H), 5.59 (s, 2H), 2.49 (s, 3H).

Example 11 Preparation of methyl 2-((4-formyl-6-methoxypyridin-3-yloxy)methyl)imidazo[1,2-a]pyridine-8-carboxylate (Compound 53)

¹H NMR (400 MHz, CDCl3) δ 10.52 (s, 1H), 8.32 (dd, J=6.7, 1.3 Hz, 1H), 8.17 (s, 1H), 8.03 (dd, J=7.2, 1.3 Hz, 1H), 7.76 (s, 1H), 7.11 (s, 1H), 6.94 (t, J=7.0 Hz, 1H), 5.53 (s, 2H), 4.06 (s, 3H), 3.93 (s, 31H).

Example 12 Preparation of 2-methoxy-5-((3-methyl-[1,2,4]triazolo[4,3-a]pyridin-8-yl)methoxy)isonicotinaldehyde (Compound 58)

¹H NMR (400 MHz, CDCl3) δ 10.53 (s, 1H), 8.14 (s, 1H), 7.89 (d, J=6.9 Hz, 1H), 7.44 (dd, J=6.8, 1.1 Hz, 1H), 7.11 (s, 1H), 6.94 (t, J=6.9 Hz, 1H), 5.67 (s, 2H), 3.92 (s, 3H), 2.80 (s, 3H).

Example 13 Preparation of 5-((2-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (Compound 134)

¹H NMR (400 MHz, CDCl3) δ 10.47 (s, 1H), 8.53 (d, J=2.1 Hz, 1H), 8.48 (d, J=4.7 Hz, 1H), 8.19 (d, J=7.8 Hz, 1H), 8.10 (s, 1H), 7.75 (s, 1H), 7.35 (dd, J=7.7, 4.7 Hz, 1H), 7.12 (s, 1H), 6.51 (dd, J=2.5, 1.8 Hz, 1H), 5.75 (s, 2H), 3.93 (s, 3H).

Example 14 Preparation of 5-((2-(1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (Compound 65)

Step 1:

To a solution of 2-bromonicotinic acid (4.0 g, 20 mmol) and triethylamine (3.34 mL, 24 mmol, 1.2 eq.) in THF (100 mL) was added i-butyl chloroformate (3.12 mL, 24 mmol, 1.2 eq.) at 0° C. The mixture was stirred at 0° C. for 10 min and filtered. To this filtrate was added a suspension of NaBH₄ (1.52 g, 40 mmol, 2 eq.) in water (1.0 mL) at 0° C. The mixture was stirred for 30 min, added water (3 mL), continued to stir for 2 h, and concentrated to dryness. The crude was purified on silica gel using a mixture of ethylacetate and hexanes as eluent to give (2-bromopyridin-3-yl)methanol (3.4 g, 90%) as a white solid. LRMS (M+H⁺) m/z 188.0.

Step 2:

To (2-bromopyridin-3-yl)methanol (380 mg, 2 mmol) in DCM (5 mL) was added SOCl₂ (1 mL) at rt. The reaction mixture was stirred at rt for 4 h and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give an off-white solid (480 mg), which was used for next step without further purification.

Step 3:

A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (306 mg, 2 mmol, 1 eq.), 2-bromo-3-(chloromethyl)pyridine (crude above, 2 mmol), and K₂CO₃ (828 mg, 6 mmol, 3 eq.) in DMF (1.0 mL) was heated at 50° C. for 2 h. The mixture was cooled and added to water (50 mL) dropwise. The precipitate was filtered, washed with water, dried under high vacuo to give 5-((2-bromopyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (350 mg, 85%) as an yellow solid. ¹H NMR (400 MHz; CDCl₃) δ=10.51 (s, 1 H), 8.42 (dd, 1 H), 8.09 (s, 1 H) 7.91 (d, 1 H), 7.40 (dd, 1 H), 7.15 (s, 1 H), 5.27 (s, 2 H), 3.95 (s, 3 H). LRMS (M+H⁺) m/z 323.0.

Step 4:

5-((2-bromopyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (258 mg, 0.8 mmol, 1 equiv), 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-ylboronic acid (233 m, 0.96 mmol, 1.2 equiv), Pd(PPh₃)₄ (92 mg, 0.08 mmol, 0.1 equiv), K₂CO₃ (331 mg, 2.4 mmol, 3 equiv) in a round bottom flask were added dioxane (8 mL) and water (2 mL). The mixture was heated 2 h at 90° C., cooled, filtered, and concentrated. The crude was purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-methoxy-5-((2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (208 mg, 79%) as a white solid. ¹H NMR (400 MHz; CDCl₃) δ=10.54 (s, 1 H), 8.85 (d, 1 H), 8.18 (d, 1 H) 8.03 (s, 1 H), 7.73 (d, 1 H), 7.56 (dd, 1 H), 7.21 (s, 1 H), 6.60 (d, 1 H), 5.79 (s, 2 H), 5.27 (s, 2 H), 4.01 (s, 3 H), 3.65 (t, 2 H), 0.88 (t, 2 H), 0.05 (s, 9 H). LRMS (M+H⁺) m/z 441.2.

Step 5:

To 2-methoxy-5-((2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (120 mg, 0.27 mmol, 1 equiv) suspended in EtOH (1 mL) was added HCl (1.0 mL, 3 N). The solution turned homogeneous and the mixture was stirred at rt overnight. The EtOH was partially removed by blowing in N₂ gas and the precipitate was collected. The solid was washed with acetonitrile and EtOAc and dried under high vacuo to give 5-((2-(1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde dihydrochloride (100 mg, 96%) as a white solid. ¹H NMR (400 MHz; DMSO, 80° C.) δ=10.27 (s, 1 H), 8.68 (br, 1 H), 8.32 (br, 1 H), 8.22 (s, 1 H), 7.82 (br, 1 H), 7.57 (br, 1 H), 7.00 (br, 2 H), 5.75 (s, 2 H), 3.89 (s, 3 H). LRMS (M+H⁺) m/z 311.1.

Examples 15-22 were synthesized according to Example 14.

Example 15 Preparation of 5-((2-bromopyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (Compound 63)

¹H NMR (400 MHz, CDCl3) δ 10.51 (s, 1H), 8.41 (dd, J=4.7, 1.8 Hz, 1H), 8.09 (s, 1H), 7.91 (dd, J=7.6, 1.6 Hz, 1H), 7.39 (dd, J=7.6, 4.8 Hz, 1H), 7.15 (s, 1H), 5.27 (s, 2H), 3.95 (s, 31H).

Example 16 Preparation of 5-((5-bromopyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (Compound 66)

¹H NMR (400 MHz, CDCl3) δ 10.47 (s, 1H), 8.73 (s, 1H), 8.65 (s, 1H), 8.07 (s, 1H), 7.99 (s, 1H), 7.15 (s, 1H), 5.22 (s, 2H), 3.95 (d, J=0.8 Hz, 3H).

Example 17 Preparation of 2-methoxy-5-((5-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 74)

¹H NMR (400 MHz, CDCl3) δ 10.44 (s, 1H), 8.75 (dd, J=9.0, 2.1 Hz, 2H), 8.11 (s, 1H), 7.88 (t, J=2.1 Hz, 1H), 7.58 (d, J=1.9 Hz, 1H), 7.13 (s, 1H), 6.43 (d, J=1.9 Hz, 1H), 5.30 (s, 2H), 3.95 (s, 3H), 3.94 (s, 3H).

Example 18 Preparation of 5-((2-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (Compound 143)

¹H NMR (400 MHz, CDCl₃) δ 10.40 (s, 1H), 8.69 (dd, J=4.8, 1.7 Hz, 1H), 7.94 (s, 1H), 7.92 (dd, J=7.8, 1.7 Hz, 1H), 7.57 (s, 1H), 7.29 (dd, J=7.8, 4.8 Hz, 2H), 7.10 (s, 1H), 5.24 (s, 2H), 3.92 (s, 3H), 3.88 (s, 3H), 2.42 (s, 3H).

Example 19 Preparation of 5-((2-(1-ethyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (Compound 149)

¹H NMR (400 MHz, CDCl3) δ 10.32 (s, 1H), 8.68 (dd, J=4.8, 1.6 Hz, 1H), 7.95 (dd, J=7.9, 1.6 Hz, 1H), 7.84 (s, 1H), 7.50 (d, J=1.9 Hz, 1H), 7.36 (dd, J=7.9, 4.8 Hz, 1H), 7.03 (s, 1H), 6.32 (d, J=1.9 Hz, 1H), 5.09 (s, 2H), 4.21 (q, J=7.2 Hz, 2H), 3.83 (s, 3H), 1.32 (t, J=7.2 Hz, 3H).

Example 20 Preparation of 2-methoxy-5-((2-phenylpyridin-3-yl)methoxy) isonicotinaldehyde (Compound 159)

¹H NMR (400 MHz, CDCl3) δ 10.26 (s, 1H), 8.63 (dd, J=4.8, 1.6 Hz, 1H), 7.88 (dd, J=7.8, 1.6 Hz, 1H), 7.78 (s, 1H), 7.48-7.44 (m, 2H), 7.41-7.34 (m, 3H), 7.28 (dd, J=7.8, 4.8 Hz, 1H), 6.99 (s, 1H), 5.12 (s, 2H), 3.80 (s, 3H).

Example 21 Preparation of 2-methoxy-5-((2-(o-tolyl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 162)

¹H NMR (400 MHz, CDCl3) δ 10.36 (s, 1H), 8.71 (dd, J=4.8, 1.6 Hz, 1H), 7.99 (dd, J=7.8, 1.6 Hz, 1H), 7.80 (s, 1H), 7.40 (dd, J=7.8, 4.8 Hz, 1H), 7.36-7.29 (m, 2H), 7.28-7.23 (m, 1H), 7.23-7.18 (m, 1H), 7.06 (s, 1H), 4.98 (s, 2H), 3.89 (s, 3H), 2.13 (s, 3H).

Example 22 Preparation of 2-methoxy-5-((2′-methoxy-[2,3′-bipyridin]-3-yl)methoxy)isonicotinaldehyde (Compound 163)

¹H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 8.71 (dd, J=4.8, 1.4 Hz, 1H), 8.28 (dd, J=5.0, 1.9 Hz, 1H), 7.96 (dd, J=7.8, 0.9 Hz, 1H), 7.82 (s, 1H), 7.74 (dd, J=7.3, 1.9 Hz, 1H), 7.41 (dd, J=7.8, 4.8 Hz, 1H), 7.09-7.03 (m, 2H), 5.14 (s, 2H), 3.96 (s, 3H), 3.89 (s, 3H).

Example 23 Preparation of 2-methoxy-5-((2-(1-((2-(trimethylsilyl) ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 193)

¹H NMR (400 MHz, CDCl3) δ 10.54 (s, 1H), 8.84 (dd, J=4.8, 1.6 Hz, 1H), 8.14 (dd, J=7.9, 1.6 Hz, 1H), 8.03 (s, 1H), 7.72 (d, J=1.7 Hz, 1H), 7.55 (dd, J=7.9, 4.8 Hz, 1H), 7.21 (s, 1H), 6.60 (d, J=1.8 Hz, 1H), 5.79 (s, 2H), 5.27 (s, 2H), 4.01 (s, 3H), 3.66-3.59 (m, 2H), 0.92-0.80 (m, 2H), 0.00 (s, 9H).

Example 24 Preparation of 2-methoxy-5-(quinolin-3-ylmethoxy)isonicotinaldehyde (Compound 80)

¹H NMR (400 MHz, CDCl3) δ 10.50 (s, 1H), 9.03 (d, J=2.2 Hz, 1H), 8.27 (d, J=1.3 Hz, 1H), 8.17 (d, J=8.5 Hz, 1H), 8.15 (s, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.79 (ddd, J=8.4, 6.9, 1.4 Hz, 1H), 7.63 (ddd, J=8.1, 7.0, 1.2 Hz, 1H), 7.14 (s, 1H), 5.42 (s, 2H), 3.94 (s, 3H).

Example 25 Preparation of 5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinic acid (Compound 79)

Step 1

A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (352 mg, 2.29 mmol, 1 eq.), methyl 5-(chloromethyl)nicotinate hydrochloride (506 mg, 2.29 mmol, 1 eq.), and K₂CO₃ (1.26 g, 9.16 mmol, 4 eq.) in DMF (8.0 mL) was heated at 60° C. for 3 h. The mixture was cooled and added into water (50 mL) dropwise. The precipitate was filtered, washed with water, and dried to give methyl 5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinate (350 mg, 85%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 10.47 (s, 1H), 9.26 (d, J=2.0 Hz, 1H), 8.90 (d, J=2.2 Hz, 1H), 8.42 (t, J=2.1 Hz, 1H), 8.09 (s, 1H), 7.15 (s, 1H), 5.29 (s, 21H), 4.01 (s, 3H), 3.95 (s, 3H). LRMS (M+H⁺) m/z 303.1.

Step 2

To 5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinate (96 mg, 0.32 mmol, 1 eq.) in a mixture of MeOH/THF (1/3, 8.0 mL) was added NaOH (3 N, 1.7 ml, 5.1 mmol, 16 eq.). The mixture was stirred at rt for 2 h, acidified to pH 3, extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na₂SO₄ and concentrated to give 5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinic acid (86 mg, 93%) as a white solid. ¹H NMR (400 MHz, DMSO) δ 13.55 (s, 1H), 10.34 (s, 1H), 9.06 (d, J=1.9 Hz, 1H), 8.96 (d, J=2.0 Hz, 1H), 8.42 (t, J=2.0 Hz, 1H), 8.34 (s, 1H), 7.02 (s, 1H), 5.44 (s, 2H), 3.86 (s, 3H). LRMS (M+H⁺) m/z 289.1.

Examples 26-35 were synthesized according to the procedure in Example 25.

Example 26 Preparation of methyl 4-(((3-formylpyridin-3-yl)oxy)methyl)benzoate (Compound 164)

¹H NMR (400 MHz, CDCl3) δ 10.44 (s, 1H), 8.46 (dd, J=4.3, 0.6 Hz, 1H), 8.11 (d, J=8.1 Hz, 2H), 7.58 (d, J=8.0 Hz, 2H), 7.50-7.40 (m, 2H), 5.33 (s, 2H), 3.95 (s, 3H).

Example 27 Preparation of 4-(((2-formyl-6-methylpyridin-3-yl)oxy)methyl)benzoic acid (Compound 165)

¹H NMR (400 MHz, CDCl₃) δ 10.42 (s, 1H), 8.16 (d, J=8.2 Hz, 2H), 7.61 (d, J=8.1 Hz, 2H), 7.33 (d, J=1.8 Hz, 2H), 5.32 (s, 2H), 2.61 (s, 3H).

Example 28 Preparation of 4-(((2-formylpyridin-3-yl)oxy)methyl)benzoic acid (Compound 166)

¹H NMR (400 MHz, CDCl₃) δ 10.35 (s, 1H), 8.38 (dd, J=4.3, 1.2 Hz, 1H), 8.08 (d, J=8.3 Hz, 2H), 7.54 (d, J=8.2 Hz, 2H), 7.42-7.32 (m, 2H), 5.26 (s, 2H).

Example 29 Preparation of methyl 3-(((4-formylpyridin-3-yl)oxy)methyl)benzoate (Compound 167)

¹H NMR (400 MHz, CDCl₃) δ 10.60 (s, 1H), 8.64 (s, 1H), 8.46 (d, J=4.7 Hz, 1H), 8.16 (s, 1H), 8.08 (d, J=7.8 Hz, 1H), 7.71-7.61 (m, 2H), 7.54 (t, J=7.7 Hz, 1H), 5.38 (s, 2H), 3.96 (s, 3H).

Example 30 Preparation of methyl 3-(((2-formyl-6-methylpyridin-3-yl)oxy)methyl)benzoate (Compound 168)

¹H NMR (400 MHz, CDCl₃) δ 10.40 (s, 1H), 8.11 (s, 1H), 8.02 (d, J=7.8 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.35 (d, J=8.7 Hz, 1H), 7.29 (d, J=8.7 Hz, 1H), 5.26 (s, 2H), 3.93 (s, 3H).

Example 31 Preparation of 3-(((4-formylpyridin-3-yl)oxy)methyl)benzoic acid (Compound 169)

¹H NMR (400 MHz, DMSO) δ 13.21-12.87 (br, 1H), 10.45 (s, 1H), 8.82 (s, 1H), 8.43 (d, J=4.8 Hz, 1H), 8.11 (s, 1H), 7.94 (d, J=7.6 Hz, 1H), 7.81 (d, J=7.1 Hz, 1H), 7.63-7.46 (m, 2H), 5.52 (s, 2H).

Example 32 Preparation of 3-(((2-formyl-6-methylpyridin-3-yl)oxy)methylbenzoic acid (Compound 170)

¹H NMR (400 MHz, DMSO) δ 12.83 (s, 1H), 9.99 (s, 1H), 7.87 (s, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.60-7.50 (m, 2H), 7.38-7.30 (m, 2H), 5.16 (s, 2H).

Example 33 Preparation of 3-(((2-formylpyridin-3-yl)oxy)methyl)benzoic acid (Compound 171)

¹H NMR (400 MHz, DMSO) δ 13.04 (s, 1H), 10.23 (s, 1H), 8.40 (d, J=4.4 Hz, 1H), 8.10 (s, 1H), 7.93 (d. J=7.7 Hz, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.80 (d, J=7.7 Hz, 1H), 7.68 (dd, J=8.6, 4.4 Hz, 1H), 7.57 (t, J=7.7 Hz, 1H), 5.41 (s, 2H).

Example 34 Preparation of 3-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)benzoic acid (Compound 203)

¹H NMR (400 MHz, CDCl3) δ 10.27 (s, 1H), 7.97 (s, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.85 (s, 1H), 7.48 (d, J=7.7 Hz, 1H), 7.32 (t, J=7.7 Hz, 1H), 6.89 (s, 1H), 5.05 (s, 2H), 3.69 (s, 3H).

Example 35 Preparation of tert-butyl 4-((2-formyl-6-methylpyridin-3-yloxy)methyl)-1H-indazole-1-carboxylate (Compound 86)

The title compound was prepared as for Example 34 above.

¹H NMR (400 MHz, CDCl3) δ 10.35 (s, 1H), 8.40 (s, 1H), 8.23 (d, J=8.6 Hz, 1H), 7.57 (dd, J=8.4, 7.3 Hz, 1H), 7.43 (d, J=7.2 Hz, 1H), 7.37 (d, J=8.6 Hz, 1H), 7.30 (d, J=8.6, 1H), 5.58 (s, 2H), 2.58 (s, 3H), 1.75 (s, 9H).

Example 36 Preparation of 5-methoxy-2-((1-methyl-1H-indazol-4-yl)methoxy)isonicotinaldehyde (Compound 115)

Step 1

To a mixture of 1-methyl-1H-indazole-4-carbaldehyde (180 mg, 1.12 mol) in THF (10 mL) was added NaBH₄ (85 mg, 2.24 mmol) at r.t. The reaction mixture was stirred at r.t. for 1 h, acidified to pH 3, and extracted with EtOAc. The combined organic layer was washed with saturated sodium bicarbonate solution and brine, dried over Na₂SO₄, filtered, and concentrated to give a crude solid (191 mg), which was used for next step without further purification.

Step 2

To (1-methyl-1H-indazol-4-yl)methanol (191 mg) in DCM (5 mL) was added SOCl₂ (2 mL) at rt. The reaction mixture was stirred at rt for 4 h and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give an off-white solid (210 mg), which was used for next step without further purification.

Step 3

A mixture of 2-hydroxy-5-methoxyisonicotinaldehyde (170 mg, 1.12 mmol), 4-(chloromethyl)-1-methyl-1H-indazole (1.12 mmol), and K₂CO₃ (618 mg, 4.48 mmol) is refluxed in CH₃CN (20 mL) for 2 h. The mixture is filtered and the solid is washed with DCM. The filtrate is concentrated and purified on silica gel using a mixture of EtOAc and MeOH as eluent to give 5-methoxy-2-((1-methyl-1H-indazol-4-yl)methoxy)isonicotinaldehyde as a white solid.

Examples 37-45 were prepared according to Example 36.

Example 37 Preparation of 2-methoxy-5-((1-methyl-1H-indazol-4-yl)methoxy)isonicotinaldehyde (Compound 84)

¹H NMR (400 MHz, CDCl3) δ 10.46 (s, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 7.48-7.38 (m, 2H), 7.22 (dd, J=6.0, 0.8 Hz, 1H), 7.10 (s, 1H), 5.55 (s, 2H), 4.13 (s, 3H), 3.91 (s, 3H).

Example 38 Preparation of 6-methyl-3-((1-methyl-1H-indazol-6-yl)methoxy)picolinaldehyde (Compound 91)

¹H NMR (400 MHz, CDCl3) δ 10.43 (s, 1H), 7.98 (d, J=0.9 Hz, 1H), 7.75 (dd, J=8.3, 0.8 Hz, 1H), 7.60 (d, J=0.8 Hz, 1H), 7.39 (d, J=8.9 Hz, 1H), 7.30 (d, J=9.0 Hz, 1H), 7.18 (dd, J=8.3, 1.3 Hz, 1H), 5.37 (s, 2H), 4.10 (s, 3H), 2.58 (s, 3H).

Example 39 Preparation of 6-methyl-3-((1-methyl-1H-indazol-7-yl)methoxy)picolinaldehyde (Compound 92)

¹H NMR (400 MHz, CDCl3) δ 10.28 (s, 1H), 8.02 (s, 1H), 7.77 (dd, J=8.1, 1.0 Hz, 1H), 7.49 (d, J=8.6 Hz, 1H), 7.38 (dd, J=7.0, 1.0 Hz, 1H), 7.34 (d, 3-8.6 Hz, 1H), 7.12 (dd, J=8.1, 7.0 Hz, 1H), 5.56 (s, 2H), 4.35 (s, 3H), 2.60 (s, 3H).

Example 40 Preparation of 3-(isoquinolin-1-ylmethoxy)-6-methylpicolinaldehyde (Compound 93)

¹H NMR (400 MHz, CDCl3) δ 10.36 (s, 1H), 8.52 (d, J=5.7 Hz, 1H), 8.48 (d, J=9.2 Hz, 1H), 7.88 (d, J=7.5 Hz, 1H), 7.77-7.66 (m, 4H), 7.27 (d, J=8.9 Hz, 1H), 5.86 (s, 2H), 2.55 (s, 3H).

Example 41 Preparation of 5-(benzo[d]oxazol-4-ylmethoxy)-2-methoxyisonicotinaldehyde (Compound 103)

¹H NMR (400 MHz, CDCl3) δ 10.51 (s, 1H), 8.18 (d, J=7.3 Hz, 2H), 7.63 (dd, J=8.1, 1.0 Hz, 1H), 7.52 (d, J=7.1 Hz, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.11 (d, J=0.5 Hz, 1H), 5.65 (s, 2H), 3.92 (s, 3H).

Example 42 Preparation of 3-((1,5-naphthyridin-4-yl)methoxy)-6-methylpicolinaldehyde (Compound 106)

¹H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 9.15 (d, J=2.1 Hz, 1H), 9.05 (dd, J=4.2, 1.6 Hz, 1H), 8.52 (d, J=1.1 Hz, 1H), 8.47 (d, J=8.5 Hz, 1H), 7.71 (dd, J=8.5, 4.2 Hz, 1H), 7.44 (d, J=8.6 Hz, 1H), 7.35 (d, J=8.6 Hz, 1H), 5.50 (s, 2H), 2.62 (s, 3H).

Example 43 Preparation of 6-methyl-3-((1-methyl-1H-indazol-5-yl)methoxy)picolinaldehyde (Compound 108)

¹H NMR (400 MHz, CDCl3) δ 10.43 (s, 1H), 8.01 (s, 1H), 7.81 (s, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.45 (d, J=8.7 Hz, 1H), 7.42 (d, J=8.6 Hz, 1H), 7.30 (d, J=8.6 Hz, 1H), 5.34 (s, 2H), 4.11 (d, J=0.5 Hz, 3H), 2.59 (s, 31H).

Example 44 Preparation of 6-methyl-3-(quinolin-5-ylmethoxy)picolinaldehyde (Compound 119)

¹H NMR (400 MHz, DMSO) δ 10.13 (s, 1H), 8.96 (dd, J=4.2, 1.6 Hz, 1H), 8.64 (d, J=8.4 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.97 (d, J=8.7 Hz, 1H), 7.91 (d, J=7.2 Hz, 1H), 7.80 (dd, J=8.4, 7.1 Hz, 1H), 7.61 (dd, J=8.6, 4.2 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 5.78 (s, 2H), 2.49 (s, 3H).

Example 45 Preparation of 2-methoxy-5-(quinolin-5-ylmethoxy)isonicotinaldehyde (Compound 120)

¹H NMR (400 MHz, CDCl3) δ 10.23 (s, 1H), 8.94 (dd, J=4.3, 1.5 Hz, 1H), 8.43 (d, J=8.5 Hz, 1H), 8.16 (d, J=14.1 Hz, 1H), 8.13 (s, 2H), 7.68 (dd, J=8.3, 7.2 Hz, 1H), 7.61 (d, J=6.7 Hz, 1H), 7.47 (dd, J=8.6, 4.3 Hz, 1H), 7.02 (s, 1H), 5.56 (s, 2H), 3.84 (s, 3H).

Example 46 Preparation of 2-methoxy-5-((2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 129)

Step 1

To a mixture of (2-bromopyridin-3-yl)methanol (20.0 g, 106.4 mmol, 1 eq.; refer to example 14) and imidazole (14.5 g, 212.8 mmol, 2 eq.) in DMF (50.0 mL) was added TBSCl (19.2 g, 150.7 mmol, 1.2 eq.) at rt. The mixture was stirred at rt for 1 h and diluted with a mixture of water (100 mL) and EtOAc (300 mL). The organic layer was washed with NH₄Cl_((sat.)) solution and brine, dried over Na₂SO₄, concentrated, and purified on silica gel using 10% EtOAc/hexanes as eluent to give 2-bromo-3-((tert-butyldimethylsilyloxy)methyl)pyridine (30.1 g, 94%) as a colorless oil. LRMS (M+H⁺) m/z 302.0.

Step 2

A mixture of 2-bromo-3-((tert-butyldimethylsilyloxy)methyl)pyridine (30.1 g, 100.0 mmol, 1 eq.) and Zn(CN)₂ (23.5 g, 200.0 mmol, 2.0 eq.) in DMF (100.0 mL) was purged with N₂ for 5 min and added Pd(PPh₃)₄ (5.78 g, 5.0 mmol, 0.05 eq.). The mixture was heated at 120° C. for 2 h under N₂, cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3-((tert-butyldimethylsilyloxy)methyl)picolinonitrile (20.4 g, 82%) as a colorless oil. LRMS (M+H⁺) m/z 249.1.

Step 3:

Methylmagnesium bromide (3M/ether, 41.0 mL, 123.4 mmol) was added to a stirred solution of 3-((tert-butyldimethylsilyloxy)methyl)picolinonitrile (20.4 g, 82.25 mmol) in THF (100.0 mL) at −78° C. The reaction mixture was warm to rt, quenched with aqueous citric acid solution, and extracted with EtOAc (50 mL) twice. The combined organic layers were washed with NaHCO_(3 (sat)) solution and brine, dried over Na₂SO₄, concentrated, and purified on silica gel using a mixture of EtOAc/hexanes as eluent to give 1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)ethanone (12.9 g, 59%) as a colorless oil. LRMS (M+H⁺) m/z 266.2.

Step 4:

1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)ethanone (10.8 g, 40.75 mmol) in dimethoxy-N,N-dimethylmethanamine (15.0 mL) was heated to reflux for 3 days. The mixture was concentrated and used for next step without further purification. LRMS (M+H⁺) m/z 321.1.

Step 5

To (E)-1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-3-(dimethylamino)prop-2-en-1-one (crude above, 966.4 mg, 3.02 mmol, 1 eq.) in EtOH (10 mL) was added methylhydrazine (1.0 mL) at rt. The mixture was heated at 80° C. for 2 h, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give a mixture of regio-isomers (420 mg; 46% for 2 steps). LRMS (M+H⁺) m/z 304.2.

Step 6

To a mixture of 3-((tert-butyldimethylsilyloxy)methyl)-2-(1-methyl-1H-pyrazol-5-yl)pyridine and 3-((tert-butyldimethylsilyloxy)methyl)-2-(1-methyl-1H-pyrazol-3-yl)pyridine (420 mg, 1.38 mmol) in MeOH (20 mL) was added HCl (4 N, 2.0 mL). The mixture was stirred at rt for 1 h, concentrated, and diluted with EtOAc (50 mL) and NaHCO_(3(sat)) solution (10 mL). The layers were separated and aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na₂SO₄, concentrated, and purified on silica gel using EtOAc as eluent to give (2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol (187 mg, 72%) and (2-(1-methyl-1H-pyrazol-3-yl)pyridin-5-yl)methanol (55 mg, 21%) as white solids. Data for 2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol: ¹H NMR (400 MHz; CDCl₃) 8.58 (d, 1 H), 7.91 (d, 1 H), 7.46 (s, 1 H), 7.30 (dd, 1 H), 6.36 (s, 1 H), 4.62 (d, 2 H), 3.83 (s, 3 H), 2.1 (t, 1 H). LRMS (M+H⁺) m/z 190.1; data for (2-(1-methyl-1-pyrazol-3-yl)pyridin-5-yl)methanol: ¹H NMR (400 MHz; CDCl₃) 8.60 (d, 1 H), 7.70 (d, 1 H), 7.47 (s, 1 H), 7.22 (dd, 1 H), 6.99 (s, 1 H), 5.91 (t, 1 H), 4.68 (d, 2 H), 4.01 (s, 3 H). LRMS (M+H⁺) m/z 190.1

Step 7

To (2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol (182 mg, 0.96 mmol) in DCM (5 mL) was added SOCl₂ (1.5 mL) at rt. The reaction mixture was stirred at rt for 4 h and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give 3-(chloromethyl)-2-(1-methyl-1H-pyrazol-5-yl)pyridine (236 mg) as an off-white solid, which was used for next step without further purification.

Step 8

A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (147 mg, 0.96 mmol, 1 eq.), 3-(chloromethyl)-2-(1-methyl-1H-pyrazol-5-yl)pyridine hydrochloride (236 mg, 0.96 mmol, 1 eq.), and K₂CO₃ (532 mg, 3.85 mmol, 3 eq.) in DMF (3.0 mL) was heated at 70° C. for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-methoxy-5-((2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (232.5 mg, 75%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 10.40 (s, 1H), 8.77 (dd, J=4.7, 1.7 Hz, 1H), 8.03 (dd, J=7.9, 1.7 Hz, 1H), 7.93 (s, 1H), 7.55 (d, J=1.9 Hz, 1H), 7.44 (dd, J=7.9, 4.8 Hz, 1H), 7.11 (d, J=0.4 Hz, 1H), 6.43 (d, J=1.9 Hz, 1H), 5.20 (s, 2H), 3.97 (s, 3H), 3.92 (s, 3H). LRMS (M+H⁺) m/z 325.1.

1H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 8.77 (dd, J=4.7, 1.7 Hz, 1H), 8.03 (dd, J=7.9, 1.7 Hz, 1H), 7.93 (s, 1H), 7.55 (d, J=1.9 Hz, 1H), 7.44 (dd, J=7.9, 4.8 Hz, 1H), 7.11 (d, J=0.4 Hz, 1H), 6.43 (d, J=1.9 Hz, 1H), 5.20 (s, 2H), 3.97 (s, 3H), 3.92 (s, 3H).

Example 47 Preparation of 2-methoxy-5-((2-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 130)

The title compound was prepared according to the procedure in Example 46.

¹H NMR (400 MHz, CDCl3) δ 10.49 (s, 1H), 8.66 (dd, J=4.7, 1.3 Hz, 1H), 8.11 (s, 1H), 8.03 (dd, J=7.8, 1.0 Hz, 1H), 7.45 (d, J=2.3 Hz, 1H), 7.31 (dd, J=7.9, 4.8 Hz, 1H), 7.13 (s, 1H), 6.97 (d, J=2.0 Hz, 1H), 5.73 (s, 2H), 3.95 (s, 3H), 3.93 (s, 3H).

Example 48 Preparation of 5-((2-(2H-tetrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (Compound 131)

Step 1:

To a mixture of 5-((2-bromopyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (100 mg, 0.31 mmol, 1 equiv), Zn (CN)₂ (71 mg, 0.62 mmol, 2.0 equiv), Pd(PPh₃)₄ (72 mg, 0.06 mmol, 0.2 equiv) in a 5 mL microwave tube was added DMF (2 mL). The mixture was heated 15 min at 125° C. in a microwave reactor. The solid was filtered off and the filtrate was concentrated to dryness. The crude was purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)picolinonitrile (71 mg, 84%) as a white solid. ¹H NMR (400 MHz; CDCl₃) δ=10.54 (s, 1 H), 8.86 (d, 1 H), 8.22 (s, 1 H), 8.20 (d, 1 H), 7.74 (dd, 1 H), 6.37 (s, 1H) 5.52 (s, 2 H), 4.04 (s, 3 H). LRMS (M+H⁺) m/z 270.1.

Step 2:

To TEA hydrochloride salt (123 mg, 0.89 mmol, 4 equiv.) and 3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)picolinonitrile (70 mg, 0.26 mmol, 1 equiv.) in chlorobenzene (5.0 mL) was added NaN₃ (48 mg, 0.89 mmol, 4 equiv.) at rt. The mixture was heated to 110° C. for 2 h, cooled to rt, and added water (5.0 mL). The precipitate was filtered and washed with EtOAc and water and dried under high vacuo to give 5-((2-(2H-tetrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde as a white solid. ¹H NMR (400 MHz; DMSO) δ=10.23 (s, 1 H), 8.61 (d, 1 H), 8.16 (s, 1 H), 8.10 (d, 1 H), 7.38 (dd, 1 H), 6.96 (s, 1H) 5.73 (s, 2 H), 3.83 (s, 3 H). LRMS (M+H⁺) m/z 313.0.

Example 49 Preparation of 2-methoxy-5-((2-(4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 132)

Step 1:

To a mixture of 5-((2-bromopyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (100 mg, 0.31 mmol, 1 equiv), 4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-ylboronic acid (98 mg, 0.47 mmol, 1.5 equiv), Pd(PPh₃)₄ (70 mg, 0.06 mmol, 0.2 equiv), K₂CO₃ (171 mg, 1.24 mmol, 4 equiv) in a 5 mL microwave tube was added DMF (2 mL). The mixture was heated 30 min at 125° C. in a microwave reactor. The solid was filtered off and the filtrate was concentrated to dryness. The crude was purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-methoxy-5-((2-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (110 mg, 87%) as a colorless oil. LRMS (M+H⁺) m/z 409.2.

Step 2:

To 2-methoxy-5-((2-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (110 mg, 0.27 mmol, 1 equiv) suspended in EtOH (1 mL) was added HCl (1.0 mL, 3 N). The solution turned homogeneous and the mixture was stirred at rt overnight. The EtOH was partially removed by blowing in N₂ gas and basified to pH 9. The aqueous solution was extracted with EtOAc three times. The organic layer was dried over Na₂SO₄ and concentrated. The crude was purified on silica gel using a mixture of MeOH and DCM as eluent to give 2-methoxy-5-((2-(4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (40 mg, 46%) as a white solid. ¹H NMR (400 MHz; CDCl₃) δ=10.45 (s, 1 H), 8.76 (d, 1 H), 8.07 (br, 1 H), 8.05 (s, 1H), 7.53 (s, 1 H), 7.40 (dd, 1 H), 7.13 (s, 1 H), 5.52 (br, 2 H), 3.98 (s, 3 H). LRMS (M+H⁺) m/z 325.1.

Example 50 Preparation of 5-((3-(1H-pyrazol-5-yl)isoquinolin-4-yl)methoxy)-2-methoxyisonicotinaldehyde (Compound 133)

Step 1:

To a mixture of POCl₃ (0.73 mL, 7.85 mmol, 3.8 eqiv.) and DMF (0.6 g, 8.16 mmol, 4.0 equiv.) in THF was added 1,2-dihydroisoquinolin-3(4H)-one at 0° C. in portions for 5 min. The mixture was continued to stir at 0° C. for 1 h and poured into a mixture of 2 N NaOH (20 mL), ice (20 g), and toluene (20 mL). The organic phase was separated and the aqueous layer was extracted with toluene one more time. The combined organic layer was washed with water, dried over Na₂SO₄, and concentrated to half of its volume at low temperature in vacuo. To this mixture was added 2 N H₂SO₄ (20 mL) under vigorous stirring followed by ground KMnO₄ in portions. The mixture was continued to stir for another 4 h. The organic phase was separated, dried over Na₂SO₄, and concentrated to give 3-chloroisoquinoline-4-carbaldehyde (220 mg, 50% pure) as a oil, which was used for next step without further purification. LRMS (M+H⁺) m/z 192.0.

Step 2:

To 3-chloroisoquinoline-4-carbaldehyde (220 mg, crude) in THF (10 mL) was added NaBH₄ (155 mg, 4.08 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, acidified to pH 3, and extracted with EtOAc. The combined organic layers were washed with saturated sodium bicarbonate solution and brine, dried over Na₂SO₄, filtered, and concentrated to give a crude solid. The crude was purified on silica gel using a mixture of EtOAc and hexanes as eluent to give (3-chloroisoquinolin-4-yl)methanol (92 mg, 24% for three steps). LRMS (M+H⁺) m/z 194.0.

Step 3:

To (3-chloroisoquinolin-4-yl)methanol (92 mg, 0.48 mmol) in DCM (5 mL) was added SOCl₂ (mL) at rt The reaction mixture was stirred at rt for 4 h and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give an off-white solid (120 mg), which was used for next step without further purification.

Step 4:

A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (73 mg, 0.48 mmol, 1 eq.), 3-chloro-4-(chloromethyl)isoquinoline (crude above, 0.48 mmol), and K₂CO₃ (265 mg, 1.92 mmol, 4 eq.) in DMF (2.0 mL) was heated at 60° C. for 1 h. The mixture was cooled, filtered, concentrated to dryness. The crude was purified on silica gel using a mixture of EtOAc and hexanes to give 5-((3-chloroisoquinolin-4-yl)methoxy)-2-methoxyisonicotinaldehyde (22 mg, 14%) as an yellow solid. ¹H NMR (400 MHz; CDCl₃) δ=10.19 (s, 1 H), 9.05 (s, 1 H), 8.23 (s, 1 H) 8.06 (d, 1 H), 7.98 (d, 1 H), 7.76 (t, 1 H), 7.63 (t, 1 H), 7.01 (s, 1H), 5.72 (s, 2 H), 3.87 (s, 3 H). LRMS (M+H⁺) m/z 329.1.

Step 5:

To a mixture of 5-((3-chloroisoquinolin-4-yl)methoxy)-2-methoxyisonicotinaldehyde (18 mg, 0.05 mmol, 1 equiv), 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-ylboronic acid (20 mg, 0.08 mmol, 1.5 equiv), Pd(PPh₃)₄ (12 mg, 0.01 mmol, 0.2 equiv), K₂CO₃ (30 mg, 0.22 mmol, 4 equiv) in a 5 mL microwave tube were added DMF (2 mL). The mixture was heated 30 min at 125° C. in a microwave reactor. The solid was filtered off and the filtrate was concentrated to dryness. The crude was purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-methoxy-5-((3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)isoquinolin-4-yl)methoxy)isonicotinaldehyde (10 mg, 38%) as a white solid. LRMS (M+H+) m/z 491.1.

Step 6:

To 2-methoxy-5-((3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)isoquinolin-4-yl)methoxy)isonicotinaldehyde (10 mg, 0.02 mmol, 1 equiv) suspended in EtOH (1 mL) was added HCl (0.1 mL, 3 N). The solution turned homogeneous and the mixture was stirred at rt overnight. The EtOH was partially removed by blowing in N₂ gas and basified to pH 9. The aqueous solution was extracted with EtOAc three times. The organic layer was dried over Na₂SO₄ and concentrated. The crude was purified on silica gel using MeOH and DCM as eluent to give 5-((3-(1H-pyrazol-5-yl)isoquinolin-4-yl)methoxy)-2-methoxyisonicotinaldehyde (6.0 mg, 83%) as a white solid. 1H NMR (400 MHz; CDCl₃) δ 10.17 (s, 1 H), 9.25 (s, 1 H), 8.18 (s, 1 H), 8.05 (d, 1 H), 7.99 (d, 1 H), 7.73 (t, 1 H), 7.60-7.68 (m, 2 H), 7.03 (s, 1 H), 6.70 (d, 1 H), 5.85 (s, 2 H), 3.85 (s, 3 H). LRMS (M+H⁺) m/z 361.1.

Example 51 Preparation of 2-(imidazo[1,5-a]pyridin-8-ylmethoxy)-5-methoxyisonicotinaldehyde

Step 1:

To a cold solution of 3-ethoxycarbonylpyridine (25 g, 165.4 mmol, 1 eq) in DCM was slowly added mCPBA (70% wt, 198.5 mmol) and the reaction mixture was stirred at rt overnight. Reaction was cooled and diluted with DCM and then neutralized with slow addition of sat. NaHCO₃. Aqueous layer was washed with DCM (3×) and the combined organic layer was dried and evaporated to give a residue, which was purified by column chromatography (EtOAc/MeOH) to give 3-ethoxycarbonylpyridine N-oxide (13.6 g). MS: exact mass calculated for C₈H₉NO₃, 167.06; m/z found, 168 [M+H]⁺.

Step 2:

To a solution of 3-ethoxycarbonylpyridine N-oxide in 330 mL of DCM were added trimethylsilyl cyanide (TMSCN) (11.0 g, 65.9 mmol, 1.0 eq) and dimethylcarbamoyl chloride (7.1 g, 65.9 mmol, 1.0 eq) and the reaction mixture was stirred at rt for 2 days. Then 10% K₂CO₃ was slowly added to make the reaction mixture basic. Organic layer was separated, dried and evaporated to provide the crude, which was purified by column chromatography to provide compounds A (5.7 g) and B (3.5 g).

Steps 3 and 4:

To a solution of ethyl 2-cyano-3-pyridinecarboxylate (2.5 g) and conc. HCl (5 mL) in 150 mL ethanol was added 10% Pd/C (wet, 250 mg) and the reaction mixture was hydrogenated using a hydrogen balloon and stirred for 12 h. The reaction was filtered through celite and ethanol was evaporated to give ethyl 2-(aminomethyl)-3-pyridinecarboxylate HCl as a white solid which was used in the next step without further purification.

A mixture of 44.8 mL of acetic anhydride and 19.2 mL of formic acid was heated in a 50-60° C. oil bath temperature for 3 h and then cooled to rt to give formic-acetic anhydride, which was then slowly added to the solid ethyl 2-(aminomethyl)-3-pyridinecarboxylate HCl and then stirred at rt for 8 h. Excess reagent was evaporated to give a residue, which was neutralized by very slow addition of sat. NaHCO₃ solution. Solution was extracted with DCM, dried and evaporated to provide ethyl imidazo[1,5-a]pyridine-8-carboxylate as a yellow solid (crude weight 2.7 g). MS: exact mass calculated for C₁₀H₁₀N₂O₂, 190.07; m/z found, 191 [M+H]⁺.

Steps 5 and 6:

To a cold solution of lithium aluminum hydride (1.62 g, 42.4 mmol, 4.0 eq) in THF (50 mL) was added the crude ethyl imidazo[1,5-a]pyridine-8-carboxylate (2.7 g, 14.2 mmol, 1.0 eq) and the reaction mixture was heated at reflux for 2 h. The reaction was cooled and water (1.7 mL), 15% NaOH (1.7 mL) and water (5.1 mL) were slowly added. Solution was diluted with excess EtOAc and stirred at rt for 30 min. The solution was filtered and the solid was washed with ethyl acetate. Organic layers were combined, dried and solvent was removed to give crude imidazo[1,5-a]pyridine-8-methanol, which was purified by column chromatography (EtOAc/Hexane). MS: exact mass calculated for C₈H₈N₂O, 148.06; m/z found, 149 [M+H]⁺.

To a solution of imidazo[1,5-a]pyridine-8-methanol (800 mg) in chloroform (50 mL) was slowly added thionyl chloride (10 mL) and the reaction mixture was stirred at rt for 8 h. Chloroform was removed and the residue was then taken in toluene and toluene was evaporated (3×) to give a solid, which was used in the next step without further purification. MS: exact mass calculated for C₈H₇ClN₂, 166.03; m/z found, 167 [M+H]⁺.

Step 7:

To a solution of chloride (1.25 mmol, 1.0 eq), and hydroxynicotinaldehyde (1.25 mmol, 1.0 eq) in DMF (10 mL) is added K₂CO₃ (3.0 eq) and the reaction mixture was heated at 80-90° C. for 5 h. Solvent is removed and the residue is purified by column chromatography (EtOAc/MeOH).

Example 52 Preparation of 5-(imidazo[1,5-a]pyridin-8-ylmethoxy)-2-methoxyisonicotinaldehyde (Compound 140)

The title compound was prepared according to the procedure in Example 51.

¹H NMR (400 MHz, CDCl3) δ 10.47 (s, 1H), 8.21 (s, 1H), 8.11 (s, 1H), 7.97 (d, J=7.0 Hz, 1H), 7.52 (s, 1H), 7.12 (s, 1H), 6.87 (t, J=8.1 Hz, 1H), 6.62 (t, J=6.8 Hz, 1H), 5.37 (s, 2H), 3.92 (s, 3H).

Example 53 Preparation of 2-(5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-methoxypyridin-4-yl)thiazolidine (Compound 155)

To a solution of aldehyde (0.326 g, 1.15 mmol, 1 eq) and DIEA (0.15 g 1.15 mmol, 1.0 eq) in EtOH (4 mL) was added cysteamine.HCl (135 mg, 1.15 mmol, 1.0 eq) and the reaction mixture was stirred at rt for 24 h. The reaction mixture was diluted with water and the solid was filtered, washed (water) and dried. The crude was purified by column chromatography (DCM/MeOH) to give the pure material. MS: exact mass calculated for C₁₇H₁₈N₄O₂S, 342.12; m/z found, 343 [M+H]⁺.

Example 54 Preparation of 1-(2-(5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-methoxypyridin-4-yl)thiazolidin-3-yl)ethanone (Compound 156)

To a solution of aldehyde (0.900 g, 3.18 mmol, 1 eq) and DIEA) (0.45 g, 3.5 mmol, 1.1 eq) in EtOH (11 mL) was added cysteamine.HCl (0.398 g, 3.5 mmol, 1.1 eq) and the reaction mixture was stirred at rt for 24 h. Solvent was removed and the crude was directly used in the next step. To a solution of crude thiazoline (3.18 mmol) and DIEA (1.5 eq) in DCM (25 mL) at 0° C. was added acetyl chloride (1.2 eq) drop wise and the reaction mixture was stirred at room temperature for 24 h. The reaction mix was diluted with DCM and washed with saturated aq. NaHCO3. The organic layer was dried and solvent was removed to give the crude amide, which was purified by column chromatography (EtOAc/MeOH) to give the amide. MS: exact mass calculated for C19H20N4O3S, 384.13; m/z found, 385 [M+H]⁺.

Example 55 Preparation of 5-hydroxy-2-methoxyisonicotinaldehyde

Step 1

To a solution of 6-methoxypyridin-3-ol (20 g, 0.16 mol, 1 eq.) in DMF (200 mL) was added NaH (60% in mineral oil; 9.6 g, 0.24 mol, 1.5 eq.) at 0-5° C. portion-wise. Upon the completion of addition, the mixture was continued to stir at 0-5° C. for 15 min, added chloromethyl methyl ether (15.5 g, 0.19 mol, 1.2 eq.), stirred at 0-5° C. for another 20 min, and quenched with NH₄Cl_((sat.)) solution. The aqueous layer was extracted with EtOAc (3×100 mL) and the combined organic layers were washed with water and brine, dried over Na₂SO₄, concentrated, and purified on silica gel using 25% EtOAc/hexanes as eluent to give 2-methoxy-5-(methoxymethoxy)pyridine (24.1 g, 89.3%) as a colorless oil. ¹H NMR (400 MHz; CDCl₃) 7.97 (d, 1 H), 7.35 (dd, 1 H), 6.70 (d, 1 H), 5.12 (s, 2 H), 3.91 (s, 3 H), 3.51 (s, 3 H). LRMS (M+H⁺) m/z 170.1

Step 2

To a mixture of 2-methoxy-5-(methoxymethoxy)pyridine (30 g, 0.178 mol, 1 eq.) and diisopropylamine (507 uL, 3.6 mmol, 0.02 eq.) in THF (500 mL) was added methyl lithium (1.6 M/THF, 200 mL, 0.32 mol, 1.8 eq.) at −40° C. Upon the completion of addition, the mixture was warmed to 0° C., continued to stir at 0° C. for 3 h, cooled back down to −40° C. and added DMF (24.7 mL, 0.32 mol, 1.8 eq.) slowly. The mixture was then stirred at −40° C. for 1 h, quenched with a mixture of HCl (12 N, 120 mL) and THF (280 mL), warmed to rt, and added water (200 mL). The pH of the mixture was adjusted to pH 8-9 with solid K₂CO₃. The aqueous layer was extracted with EtOAc (300 mL) twice. The combined organic layers were dried over Na₂SO₄ and concentrated to give 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (33.5 g, 95.7%) as a brown solid, which was used for next step without further purification. ¹H NMR (400 MHz; CD₃OD) 7.90 (s, 1 H), 6.92 (s, 1 H), 5.64 (s, 1 H), 5.20 (s, 2 H), 3.84 (s, 3 H), 3.48 (s, 3 H). LRMS (M+H⁺) m/z 198.1

Step 3

To a solution of 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (33.5 g, 0.17 mol, 1 eq.) in THF (150 mL) was added HCl (3 N, 250 mL, 4.4 eq.). The reaction was stirred at 50° C. for 1 h, cooled to rt, and diluted with water (500 mL). The mixture was neutralized to pH 7-8 with solid K₂CO₃. The pale yellow solid was collected, washed with water, and dried to give 5-hydroxy-2-methoxyisonicotinaldehyde (17.9 g, 74.6%) as a pale yellow solid. ¹H NMR (400 MHz; DMSO) δ=10.31 (s, 1 H), 8.03 (s, 1 H), 6.89 (s, 1 H), 3.80 (s, 3 H). LRMS (M+H⁺) m/z 154.0.

Example 56 Preparation of 5-((2-(1-isopropyl-) H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (Compound 150)

Step 1:

To (E)-1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-3-(dimethylamino)prop-2-en-1-one (crude, 1.03 g, 3.22 mmol, 1 eq.; refer to Example 46) in EtOH (10 mL) was added isopropylhydrazine hydrochloride (430 mg, 3.86 mmol, 1.2 eq.). The mixture was heated at 80° C. for 2 h, cooled, added HCl (6 N, 0.5 mL), and stirred O/N. The mixture was concentrated and diluted with EtOAc (80 mL) and NaHCO_(3(sat)) (10 mL) solution. The layers were separated and the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na₂SO₄, concentrated, and purified on silica gel using EtOAc as eluent to give (2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol (500 mg, 71%) and (2-(1-isopropyl-1H-pyrazol-3-yl)pyridin-5-yl)methanol (55 mg, 25%) as pale yellow oils. Data for 2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol: ¹H NMR (400 MHz, CDCl₃) δ 8.67 (dd, J=4.7, 1.5 Hz, 1H), 8.0 (d, J=7.8 Hz, 1H), 7.61 (d, J=1.8 Hz, 1H), 7.39 (dd, J=7.8, 4.8 Hz, 1H), 6.37 (d, J=1.8 Hz, 1H), 4.67 (s, 2H), 4.55 (sep, J=6.6 Hz 1H), 1.98-2.05 (br, 1H), 1.47 (d, J=6.6 Hz, 6H). LRMS (M+H⁺) m/z 218.1 Data for (2-(1-isopropyl-1H-pyrazol-3-yl)pyridin-5-yl)methanol: ¹H NMR (400 MHz, CDCl₃) δ 8.62 (dd, J=4.8, 1.6 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.55 (d, J=2.4 Hz, 1H), 7.23 (dd, J=7.6, 4.8 Hz, 1H), 6.99 (dd, J=8.0, 6.5 Hz, 1H), 6.07 (t, J=7.6 Hz, 1H), 4.67 (d, J=7.6 Hz, 2H), 4.58 (sep, J=6.7 Hz, 1H), 1.60 (d, J=6.7 Hz, 1H). LRMS (M+H⁺) m/z 218.1

Step 2:

To (2-(1-iospropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol (560 mg, 2.58 mmol) in DCM (10 mL) was added SOCl₂ (3.0 mL) at rt. The reaction mixture was stirred at rt for 4 h and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride (700 mg) as an off-white solid, which was used for next step without further purification.

Step 3:

A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (395 mg, 2.58 mmol, 1 eq.), 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride (700 mg, 2.58 mmol, 1 eq.), and K₂CO₃ (1.4 g, 10.32 mmol, 4 eq.) in DMF (10.0 mL) was heated at 70° C. for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (590 mg, 65%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 10.41 (s, 1H), 8.76 (dd, J=4.7, 1.6 Hz, 1H), 8.04 (dd, J=7.9, 1.6 Hz, 1H), 7.90 (s, 1H), 7.61 (d, J=1.8 Hz, 1H), 7.44 (dd, J=7.9, 4.8 Hz, 1H), 7.10 (s, 1H), 6.37 (d, J=1.8 Hz, 1H), 5.14 (s, 2H), 4.65 (sep, J=6.6 Hz, 1H), 3.91 (s, 3H), 1.49 (d, J=6.6 Hz, 6H). LRMS (M+H⁺) m/z 353.1.

Step 4:

5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (980 mg, 2.78 mmol, 1 eq.) in HCl (6 N, 9.2 mL, 20 eq.) solution was freeze at −78° C. The mixture was lyophilized O/N to give 5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde bis-hydrochloride as a yellow solid. ¹H NMR (400 MHz, D₂O) δ 8.85 (dd, J=5.7, 1.3 Hz, 1H), 8.78 (d, J=8.2 Hz, 1H), 8.12 (dd, J=8.1, 5.7 Hz, 1H), 7.76 (s, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.46 (s, 1H), 6.65 (d, J=2.1 Hz, 1H), 6.09 (s, 1H), 5.09 (s, 2H), 4.24 (sep, J=6.6 Hz, 1H), 4.04 (s, 3H), 1.26 (d, J=6.6 Hz, 7H). LRMS (M+H⁺) m/z 353.1.

¹H NMR (400 MHz, CDCl₃) δ 10.41 (s, 1H), 8.76 (dd, J=4.7, 1.6 Hz, 1H), 8.04 (dd, J=7.9, 1.6 Hz, 1H), 7.90 (s, 1H), 7.61 (d, J=1.8 Hz, 1H), 7.44 (dd, J=7.9, 4.8 Hz, 1H), 7.10 (s, 1H), 6.37 (d, J=1.8 Hz, 1H), 5.14 (s, 2H), 4.65 (hept, J=6.6 Hz, 1H), 3.91 (s, 3H), 1.49 (d, J=6.6 Hz, 6H).

Examples 57-62 were prepared according to the procedure in Example 55.

Example 57 Preparation of 2-methoxy-5-((2-(1-(2-methoxyethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 172)

¹H NMR (400 MHz, DMSO) δ 13.04 (s, 1H), 10.23 (s, 1H), 8.40 (d, J=4.4 Hz, 1H), 8.10 (s, 1H), 7.93 (d, J=7.7 Hz, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.80 (d, J=7.7 Hz, 1H), 7.68 (dd, J=8.6, 4.4 Hz, 1H), 7.57 (t, J=7.7 Hz, 1H), 5.41 (s, 2H).

Example 58 Preparation of 2-methoxy-5-((2-(1-propyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 173)

¹H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 8.76 (dd, J=4.7, 1.6 Hz, 1H), 8.04 (dd, J=7.9, 1.3 Hz, 1H), 7.93 (s, 1H), 7.57 (d, J=1.8 Hz, 1H), 7.44 (dd, J=7.9, 4.8 Hz, 1H), 7.11 (s, 1H), 6.41 (d, J=1.9 Hz, 1H), 5.17 (s, 2H), 4.23 (t, J=7.4 Hz, 2H), 3.92 (s, 3H), 1.80 (sex, J=7.4 Hz, 2H), 0.81 (t, J=7.4 Hz, 3H).

Example 59 Preparation of 2-methoxy-5-((2-(1-(2,2,2-trifluoroethyl)-1-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 174)

¹H NMR (400 MHz, CDCl3) δ 10.33 (s, 1H), 8.67 (dd, J=4.8, 1.6 Hz, 1H), 7.97 (dd, J=7.9, 1.4 Hz, 1H), 7.91 (s, 1H), 7.59 (d, J=1.9 Hz, 1H), 7.38 (dd, J=7.9, 4.8 Hz, 1H), 7.05 (s, 1H), 6.47 (d, J=1.9 Hz, 1H), 5.17 (q, J=8.6 Hz, 2H), 5.11 (s, 2H), 3.85 (s, 3H).

Example 60 Preparation of 5-((2-(1-(2,2-difluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (Compound 175)

¹H NMR (400 MHz, CDCl₃) δ 10.31 (s, 1H), 8.66 (dd, J=4.8, 1.6 Hz, 1H), 7.96 (dd, J=7.9, 1.4 Hz, 1H), 7.87 (s, 1H), 7.55 (d, J=1.9 Hz, 1H), 7.36 (dd, J=7.9, 4.8 Hz, 1H), 7.02 (s, 1H), 6.42 (d, J=1.9 Hz, 1H), 6.11 (tt, J=56.0, 4.4 Hz, 1H), 5.11 (s, 2H), 4.67 (td, J=13.4, 4.4 Hz, 2H), 3.83 (s, 3H).

Example 61 Preparation of 3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)picolinaldehyde (Compound 176)

¹H NMR (400 MHz, CDCl₃) δ 10.34 (s, 1H), 8.76 (dd, J=4.7, 1.6 Hz, 1H), 8.47 (dd, J=4.4, 1.0 Hz, 1H), 8.32 (dd, J=7.9, 1.5 Hz, 1H), 7.64 (d, J=1.8 Hz, 1H), 7.49 (td, J=8.3, 4.6 Hz, 2H), 7.31 (d, J=8.5 Hz, 1H), 6.39 (d, J=1.8 Hz, 1H), 5.15 (s, 2H), 4.65 (sep, J=6.6 Hz, 1H), 1.49 (d, J=6.6 Hz, 6H).

Example 62 Preparation of 3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-6-methylpicolinaldehyde (Compound 177)

¹H NMR (400 MHz, CDCl₃) δ 10.31 (s, 1H), 8.75 (dd, J=4.7, 1.3 Hz, 1H), 8.29 (d, J=7.9 Hz, 1H), 7.64 (d, J=1.7 Hz, 1H), 7.48 (dd, J=7.9, 4.8 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.20 (d, J=8.6 Hz, 1H), 6.38 (d, J=1.7 Hz, 1H), 5.11 (s, 2H), 4.64 (sep, J=6.6 Hz, 1H), 2.61 (s, 3H), 1.49 (d, J=6.6 Hz, 6H).

Example 63 Preparation of 5-((2-(1-cyclobutyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (Compound 195)

¹H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 8.68 (dd, J=4.8, 1.6 Hz, 1H), 7.94 (dd, J=7.9, 1.6 Hz, 1H), 7.79 (s, 1H), 7.54 (d, J=1.8 Hz, 1H), 7.36 (dd, J=7.9, 4.8 Hz, 1H), 7.01 (s, 1H), 6.30 (d, J=1.8 Hz, 1H), 5.05 (s, 2H), 4.77 (quin, J=8.4 Hz, 1H), 3.82 (s, 3H), 2.74-2.56 (m, 2H), 2.32-2.15 (m, 2H), 1.87-1.73 (m, 1H), 1.72-1.59 (m, 1H).

Example 64 Preparation of 5-((2-(1-cyclohexyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (Compound 196)

¹H NMR (400 MHz, CDCl3) δ 10.33 (s, 1H), 8.68 (dd, J=4.7, 1.5 Hz, 1H), 7.96 (dd, J=7.9, 1.2 Hz, 1H), 7.81 (s, 1H), 7.51 (d, J=1.8 Hz, 1H), 7.36 (dd, J=7.9, 4.8 Hz, 1H), 7.02 (s, 1H), 6.28 (d, J=1.8 Hz, 1H), 5.05 (s, 2H), 4.10 (quin, J=7.6 Hz, 1H), 3.83 (s, 3H), 1.96-1.83 (m, J=2.9 Hz, 41H), 1.83-1.68 (m, 2H), 1.68-1.45 (m, 2H), 1.33-1.06 (m, 2H).

Example 65 Preparation of 5-((2-(1-(cyclohexylmethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (Compound 197)

¹H NMR (400 MHz, CDCl3) δ 10.43 (s, 1H), 8.76 (dd, J=4.7, 1.4 Hz, 1H), 8.04 (dd, J=7.9, 1.0 Hz, 1H), 7.93 (s, 1H), 7.58 (d, J=1.7 Hz, 1H), 7.45 (dd, J=7.9, 4.8 Hz, 1H), 7.11 (s, 1H), 6.40 (d, J=1.8 Hz, 1H), 5.16 (s, 2H), 4.13 (d, J=7.3 Hz, 2H), 3.92 (s, 3H), 1.92-1.74 (m, 1H), 1.60 (dd, J=8.2, 4.5 Hz, 3H), 1.47 (d, J=11.4 Hz, 2H), 1.21-0.98 (m, 3H), 0.91-0.71 (m, 2H).

Example 66 Preparation of 5-((2-(1-cyclopentyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (Compound 198)

¹H NMR (400 MHz, CDCl3) δ 10.42 (s, 1H), 8.77 (dd, J=4.7, 1.5 Hz, 1H), 8.04 (dd, J=7.9, 1.2 Hz, 1H), 7.90 (s, 1H), 7.60 (d, J=1.8 Hz, 1H), 7.45 (dd, J=7.9, 4.8 Hz, 1H), 7.11 (s, 1H), 6.38 (d, J=1.9 Hz, 1H), 5.15 (s, 2H), 4.74 (quin, J=7.5 Hz, 1H), 3.92 (s, 3H), 2.23-1.85 (m, 6H), 1.63-1.51 (m, 2H).

Example 67 Preparation of 2-(difluoromethoxy)-5-(imidazo[1,2-a]pyridin-8-ylmethoxy)isonicotinaldehyde (Compound 158)

Step 1:

To 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-methoxyisonicotinaldehyde (300 mg, 0.84 mmol, 1 equiv) in a vial was added HCl (6 N, 1 mL, 6 mmol). The mixture was concentrated, dried under vacuum at 60° C. O/N, cooled to rt, and dissolved in NaOH (3 N, 5 mL), filtered, and washed with with EtOAc twice. The pH of the aqueous layer was adjust to pH 6-7, filtered, and purified by RP-HPLC (Gemini 21.2×150 mm) with a mixture of CH₃CN and water (0.1% HCOOH) as eluent to give 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-oxo-1,2-dihydropyridine-4-carbaldehyde formate (82.5 mg, 31%) as an yellow solid. ¹H NMR (400 MHz, D₂O) δ 8.56 (d, J=7.1 Hz, 1H), 8.32 (s, 1H), 8.01 (d, J=2.1 Hz, 1H), 7.83 (d, J=7.2 Hz, 1H), 7.81 (t, J=2.1 Hz, 1H), 7.31 (t, J=7.2 Hz, 1H), 7.27 (s, 1H), 6.68 (s, 1H), 5.94 (s, 1H), 5.32 (s, 2H). LRMS (M+H⁺) m/z 270.1.

Step 2:

To 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-oxo-1,2-dihydropyridine-4-carbaldehyde (100 mg, 0.37 mmol, 1 equiv) in CH₃CN (10 mL) was added sodium 2-chloro-2,2-difluoroacetate (84.5 mg, 0.56 mmol, 1.5 eq.). The mixture was stirred at rt O/N and concentrated. The crude was purified on silica gel using 10% MeOH/DCM as eluent to give 2-(difluoromethoxy)-5-(imidazo[1,2-a]pyridin-8-ylmethoxy)isonicotinaldehyde (6.0 mg, 5%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 10.46 (s, 1H), 8.14 (s, 1H), 8.10 (d, J=7.0 Hz, 1H), 7.61 (s, 2H), 0.7.44 (t, J=60.0 Hz, 1H), 7.24-7.27 (m, 2H), 6.79 (t, J=7.0 Hz, 1H), 5.63 (s, 2H). LRMS (M+H⁺) m/z 320.0.

Example 68 Preparation of 2-(difluoromethoxy)-5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 178)

The title compound was prepared according to the procedure in Example 67.

¹H NMR (400 MHz, CDCl₃) δ 10.44 (s, 1H), 8.80 (d, J=3.7 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.95 (s, 1H), 7.63 (d, J=1.6 Hz, 1H), 7.47 (dd, J=7.9, 4.8 Hz, 1H), 7.33 (t, J=72.8 Hz, 1H), 6.37 (d, J=1.7 Hz, 1H), 5.21 (s, 2H), 4.67 (sep, J=6.6 Hz, 1H), 1.50 (d, J=6.6 Hz, 6H).

Example 69 Preparation of 5-((3-(1-isopropyl-1H-pyrazol-5-yl)pyridin-4-yl)methoxy)-2-methoxyisonicotinaldehyde (Compound 160)

Step 1:

To a mixture of 3-bromoisonicotinic acid (2.5 g, 12.37 mmol, 1 eq.) and TEA (3.44 mL, 24.75 mmol, 2.0 eq.) in THF (100 mL) was added methyl chloroformate (1.2 mL, 14.85 mmol, 1.2 eq.) at 0° C. The mixture was stirred at 0° C. for 10 min and filtered. To this filtrate was added a suspension of NaBH₄ (0.95 g, 24.75 mmol, 2 eq.) in water (1.0 mL) at 0° C. The mixture was stirred at 0° C. for 1 h, quenched with NH₄Cl_((aq)) solution, extracted with EtOAc twice. The combined organic layers were dried over Na₂SO₄, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give (3-bromopyridin-4-yl)methanol (1.2 g, 52%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.48 (s, 1H), 8.37 (d, J=4.9 Hz, 1H), 7.37 (d, J=4.9 Hz, 1H), 4.61 (d, J=5.5 Hz, 21H), 2.3 (t, J=5.5 Hz, 1H). LRMS (M+H⁺) m/z 188.0.

Step 2:

To a mixture of (3-bromopyridin-4-yl)methanol (150 mg, 0.8 mmol, 1 eq.), 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (226 mg, 0.96 mmol, 1.2 eq.), Pd(dppf)Cl₂ (58 mg, 0.08 mmol, 0.1 eq.), and K₂CO₃ (331 mg, 3.0 mmol, 3 eq.) in a RB flask were added dioxane (6 mL) and water (2 mL). The mixture was heated at 100° C. for 2 h, cooled, filtered, and concentrated. The crude was purified on silica gel using a mixture of EtOAc and hexanes as eluent to give (3-(1-isopropyl-1H-pyrazol-5-yl)pyridin-4-yl)methanol (75 mg, 43%) as a yellow oil. LRMS (M+H⁺) m/z 218.1.

Step 3:

(3-(1-isopropyl-1H-pyrazol-5-yl)pyridin-4-yl)methanol (75 mg, 0.35 mmol) in SOCl₂ (5 mL) was heated at 60° C. for 30 min and concentrated. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give a brown solid (95 mg), which was used for next step without further purification.

Step 4:

A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (79 mg, 0.52 mmol, 1.5 eq.), 4-(chloromethyl)-3-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride (crude above, 0.35 mmol), and K₂CO₃ (145 mg, 1.05 mmol, 3 eq.) in DMF (10.0 mL) was heated at 100° C. for 2 h. The mixture was cooled, filtered, concentrated, and purified on RP-HPLC (Gemini 21.2×150 mm) twice using a mixture of CH₃CN/water (0.1% HCOOH) as eluent to give 5-((3-(1-isopropyl-1H-pyrazol-5-yl)pyridin-4-yl)methoxy)-2-methoxyisonicotinaldehyde (6.0 mg, 5%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 10.29 (s, 1H), 8.63 (s, 1H), 8.42 (s, 1H), 7.67 (s, 1H), 7.54 (s, 1H), 7.52 (d, J=1.7 Hz, 1H), 6.96 (s, 1H), 6.15 (d, J=1.8 Hz, 1H), 4.87 (s, 2H), 4.06 (sep, J=6.6 Hz, 1H), 3.75 (s, 3H), 1.31 (d, J=6.6 Hz, 6H). LRMS (M+H⁺) m/z 353.1.

Example 70 Preparation of 5-([2,3′-bipyridin]-3-ylmethoxy)-2-methoxyisonicotinaldehyde (Compound 161)

The title compound was prepared according to the procedure in Example 69.

¹H NMR (400 MHz, CDCl3) δ 10.36 (s, 1H), 8.85 (d, J=1.7 Hz, 1H), 8.78 (dd, J=4.8, 1.6 Hz, 1H), 8.71 (dd, J=4.8, 1.5 Hz, 1H), 8.02 (dd, J=7.8, 1.5 Hz, 1H), 7.96 (dt, J=7.9, 1.9 Hz, 1H), 7.90 (s, 1H), 7.49-7.42 (m, 2H), 7.10 (s, 1H), 5.21 (s, 2H), 3.91 (s, 3H).

Example 71 Preparation of 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-(2-methoxyethoxy) isonicotinaldehyde (Compound 179)

To a mixture of 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-oxo-1,2-dihydropyridine-4-carbaldehyde (100 mg, 0.37 mmol, 1 equiv) and K₂CO₃ (153.2 mg, 1.11, 3.0 eq.) in DMF (5 mL) was added 1-bromo-2-methoxyethane (154.3 mg, 1.11 mmol, 3.0 eq.). The mixture was stirred at rt O/N, filtered, concentrated, and purified on silica gel using 10% MeOH/DCM as eluent to give 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-(2-methoxyethoxy)isonicotinaldehyde (6.0 mg, 5%) as an yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 10.45 (s, 1H), 8.08 (d, J=6.8 Hz, 1H), 8.06 (s, 1H), 7.60 (dd, J=6.8, 1.2 Hz, 2H), 7.27 (dd, J=6.9, 1.0 Hz, 1H), 7.09 (s, 1H), 6.78 (t, J=6.9 Hz, 1H), 5.58 (s, 2H), 4.35 (dd, J=5.4, 3.9 Hz, 2H), 3.66 (dd, J=5.4, 3.9 Hz, 2H), 3.36 (s, 3H). LRMS (M+H⁺) m/z 328.1.

Example 72 Preparation of 5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-(2-methoxyethoxy)isonicotinaldehyde (Compound 180)

The title compound was prepared according to the procedure in Example 71.

¹H NMR (400 MHz, CDCl₃) δ 10.40 (s, 1H), 8.76 (dd, J=4.7, 1.5 Hz, 1H), 8.04 (dd, J=7.9, 1.2 Hz, 1H), 7.87 (s, 1H), 7.61 (d, J=1.8 Hz, 1H), 7.44 (dd, J=7.9, 4.8 Hz, 1H), 7.16 (s, 1H), 6.37 (d, J=1.8 Hz, 1H), 5.14 (s, 2H), 4.65 (sep, J=6.6 Hz, 1H), 4.42 (t, J=4.8 Hz, 2H), 3.74 (t, J=4.8 Hz, 2H), 3.44 (s, 3H), 1.49 (d, J=6.6 Hz, 6H).

Example 73 Preparation of 5-((3-(1-isopropyl-1H-pyrazol-5-yl)pyrazin-2-yl)methoxy)-2-methoxyisonicotinaldehyde (Compound 181)

Step 1:

To a solution of 3-chloropyrazine-2-carboxylic acid (2.0 g, 12.70 mmol, 1.0 eq.) and TEA (3.50 mL, 25.40 mmol, 2.0 eq.) in THF (50 mL) was added methyl chloroformate (1.2 mL, 15.20 mmol, 1.2 eq.) at 0° C. The mixture was stirred at 0° C. for 10 min and filtered. To this filtrate was added a suspension of NaBH₄ (0.97 g, 25.40 mmol, 2 eq.) in water (1.0 mL) at 0° C. The mixture was stirred at 0° C. for 1 h, quenched with NH₄Cl_((aq)) solution, and extracted with EtOAc twice. The combined organic layers were dried over Na₂SO₄, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give (3-chloropyrazin-2-yl)methanol (400 mg, 22%) as a white solid. ¹H NMR (400 MHz, MeOD) δ 8.58 (d, J=2.5 Hz, 1H), 8.38 (d, J=2.5 Hz, 1H), 4.84 (s, 2H). LRMS (M+H⁺) m/z 145.1.

Step 2:

To a mixture of (3-chloropyrazin-2-yl)methanol (200 mg, 1.4 mmol, 1 eq.), 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (393 mg, 1.67 mmol, 1.2 eq.), Pd(dppf)Cl₂ (102 mg, 0.14 mmol, 0.1 eq.), and K₂CO₃ (580 mg, 4.2 mmol, 3 eq.) in a RB flask were added dioxane (6 mL) and water (2 mL). The mixture was heated at 100° C. for 1 h, cooled to rt, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give (3-(1-isopropyl-1H-pyrazol-5-yl)pyrazin-2-yl)methanol (110 mg, 36%) as a yellow oil. LRMS (M+H⁺) m/z 219.1.

Step 3:

3-(1-isopropyl-1H-pyrazol-5-yl)pyrazin-2-yl)methanol (75 mg, 0.35 mmol) in SOCl₂ (5 mL) was heated at 60° C. for 30 min and concentrated. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give a brown solid (95 mg), which was used for next step without further purification.

Step 4:

A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (110 mg, 0.60 mmol, 1.2 eq.), 2-(chloromethyl)-3-(1-isopropyl-1H-pyrazol-5-yl)pyrazine hydrochloride (crude above, 0.5 mmol, 1 eq.), and K₂CO₃ (207 mg, 1.50 mmol, 3 eq.) in DMF (15.0 mL) was heated at 100° C. for 30 min. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 5-((3-(1-isopropyl-1H-pyrazol-5-yl)pyrazin-2-yl)methoxy)-2-methoxyisonicotinaldehyde (12.0 mg, 68%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 10.31 (s, 1H), 8.73 (d, J=2.4 Hz, 1H), 8.65 (d, J=2.4 Hz, 1H), 8.05 (s, 1H), 7.61 (d, J=1.9 Hz, 1H), 7.06 (s, 1H), 6.49 (d, J=1.9 Hz, 1H), 5.32 (s, 2H), 4.68 (sep, J=6.6 Hz, 1H), 3.89 (s, 2H), 1.48 (d, J=6.6 Hz, 6H). LRMS (M+H⁺) m/z 354.1.

Example 74 Preparation of methyl 3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)picolinate (Compound 182)

To 3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)picolinic acid (55 mg, 0.17 mmol, 1 equiv) in MeOH (15 mL) was added SOCl₂ (5.0 mL). The mixture was heated to reflux O/N, concentrated, and neutralized to pH 8-9 with NaHCO_(3(sat.)) solution. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na₂SO₄, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give methyl 3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)picolinate (51.5 mg, quantitative yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 10.44 (s, 1H), 8.67 (dd, J=4.6, 1.5 Hz, 1H), 8.14 (dd, J=8.0, 1.5 Hz, 1H), 8.03 (s, 1H), 7.51 (dd, J=8.0, 4.6 Hz, 1H), 7.06 (s, 1H), 5.60 (s, 2H), 3.95 (s, 3H), 3.85 (s, 3H). LRMS (M+H⁺) m/z 303.1.

Example 75 Preparation of 5-((2-(2-hydroxypropan-2-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (Compound 183)

Step 1:

Methylmagnesium bromide (3M/ether, 2.0 mL, 5.65 mmol, 1.5 eq.) was added to a stirred solution of 3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)picolinonitrile (1180 mg, 3.76 mmol, 1 eq.) in THF (10.0 mL) at −78° C. After addition, the reaction mixture was allowed to warm to rt and quenched with aqueous citric acid solution. The aqueous layer was extracted with EtOAc (30 mL) twice. The combined organic layers were washed with NaHCO_(3(sat)) solution and brine, dried over Na₂SO₄, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 1-(3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)ethanone (776 mg, 63%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 8.66 (d, J=4.0 Hz, 1H), 8.26 (d, J=7.9 Hz, 1H), 7.82 (s, 1H), 7.54 (dd, J=8.0, 4.0 Hz, 1H), 6.95 (s, 1H), 6.23 (s, 1H), 5.59 (s, 2H), 4.22-4.04 (m, 4H), 3.90 (s, 3H), 2.79 (s, 3H). LRMS (M+H⁺) m/z 331.1.

Step 2:

Methylmagnesium bromide (3M/ether, 0.25 mL, 0.75 mmol, 3.0 eq.) was added to a stirred solution of 1-(3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)propan-1-one (82 mg, 0.25 mmol, 1 eq.) in THF (5.0 mL) at −78° C. After addition, the reaction mixture was warm to rt and quenched with aqueous citric acid solution. The aqueous layer was extracted with EtOAc (20 mL) twice. The combined organic layers were washed with NaHCO_(3(sat)) solution and brine, dried over Na₂SO₄, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-(3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)propan-2-ol (38 mg, 44%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 8.43 (dd, J=7.7, 1.6 Hz, 1H), 7.84 (dd, J=7.7, 1.5 Hz, 1H), 7.74 (s, 1H), 7.18 (dd, J=7.7, 4.7 Hz, 1H), 6.84 (s, 1H), 6.01 (s, 1H), 5.27 (s, 2H), 4.07-3.88 (m, 4H), 3.82 (s, 3H), 1.55 (s, 6H). LRMS (M+H⁺) m/z 347.1.

Step 3:

To 2-(3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)propan-2-ol (30 mg, 0.087 mmol, 1 eq.) in a RB flask was added HCl (6 N, 3.0 mL). The mixture was warmed to 40° C. O/N, cooled to rt, neutralized to pH 7-8 with NaHCO_(3(sat)) solution, and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na₂SO₄, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 5-((2-(2-hydroxypropan-2-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (10.2 mg, 99%) as a pale-yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 10.36 (s, 1H), 8.46 (dd, J=4.7, 1.6 Hz, 1H), 7.99 (s, 1H), 7.86 (dd, J=7.8, 1.5 Hz, 1H), 7.24 (dd, J=7.8, 4.7 Hz, 1H), 7.05 (s, 1H), 5.37 (s, 2H), 3.85 (s, 3H), 1.57 (s, 6H). LRMS (M+H⁺) m/z 303.1.

Example 76 Preparation of 5-hydroxy-2-(2-methoxyethoxy)isonicotinaldehyde and 5-hydroxy-2-(2-methoxyethoxy)nicotinaldehyde

Step 1

To a solution of 6-(benzyloxy)pyridin-3-ol (2.0 g, 10 mmol, 1 eq.) in DMF (20 mL) was added NaH (60% in mineral oil; 0.6 g, 15 mmol, 1.5 eq.) at 0-5° C. portion-wise. Upon the completion of addition, the mixture was continued to stir at 0-5° C. for 15 min, added chloromethyl methyl ether (0.88 g, 11 mmol, 1.1 eq.), stirred at 0-5° C. for another 20 min, and quenched with NH₄Cl_((sat.)) solution. The aqueous layer was extracted with EtOAc (3×20 mL) and the combined organic layers were washed with water and brine, dried over Na₂SO₄, concentrated, and purified on silica gel using 25% EtOAc/hexanes as eluent to give 2-(benzyloxy)-5-(methoxymethoxy)pyridine (2.1 g, 87%) as a colorless oil. LRMS (M+H⁺) m/z 246.1

Step 2

To 2-(benzyloxy)-5-(methoxymethoxy)pyridine (1.8 g, 8.71 mol) in EtOH was added Pd/C (1.0 g). The mixture was charged with H₂ (15 psi), stirred at rt for 45 min, filtered, and concentrated to give 5-(methoxymethoxy)pyridin-2-ol (1.35 g, quantitative yield) as a pale yellow solid. LRMS (M+H⁺) m/z 156.1

Step 3

To a mixture of 5-(methoxymethoxy)pyridin-2-ol (1.35 g, 8.71 mmol, 1 eq.) and K₂CO₃ (6.01 g, 43.6 mmol, 5.0 eq.) in DMF (30.0 mL) was added 1-bromo-2-methoxyethane (3.61 g, 26.1 mmol, 3 eq.). The mixture was heated at 60° C. for 2 h, cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-(2-methoxyethoxy)-5-(methoxymethoxy)pyridine (500 mg, 27%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.94 (d, J=3.0 Hz, 1H), 7.35 (ddd, J=8.9, 3.0, 1.0 Hz, 1H), 6.76 (dd, J=8.9, 1.0 Hz, 1H), 5.11 (s, 2H), 4.48-4.40 (m, 2H), 3.79-3.71 (m, 2H), 3.50 (s, 3H), 3.45 (s, 3H). LRMS (M+H⁺) m/z 214.1.

Step 4

To a mixture of 2-(2-methoxyethoxy)-5-(methoxymethoxy)pyridine (1.34 g, 6.3 mol, 1 eq.) and diisopropylamine (17.5 uL, 0.13 mmol, 0.02 eq.) in THF (50 mL) was added methyl lithium (1.6 M/THF, 7 mL, 11.3 mol, 1.8 eq.) at −40° C. Upon the completion of addition, the mixture was warmed to 0° C., continued to stir at 0° C. for 3 h, cooled back down to −40° C., and added DMF (0.83 mL, 11.3 mol, 1.8 eq.) slowly. The mixture was then stirred at −40° C. for 1 h, quenched with a mixture of HCl (12 N, 12 mL) and THF (28 mL), warmed to rt, and added water (20 mL). The pH of the mixture was adjusted to pH 8-9 with solid K₂CO₃. The aqueous layer was extracted with EtOAc (30 mL) twice. The combined organic layers were dried over Na₂SO₄, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give a mixture of 2-(2-methoxyethoxy)-5-(methoxymethoxy)isonicotinaldehyde and 2-(2-methoxyethoxy)-5-(methoxymethoxy)nicotinaldehyde (5/1, 1.27 g, 83.6%) as a pale yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 10.45 (s, 1H), 8.23 (s, 1H), 7.16 (s, 1H), 5.27 (s, 2H), 4.46 (dd, J=5.4, 3.9 Hz, 2H), 4.14 (q, J=7.1 Hz, 1H), 3.77-3.71 (m, 2H), 3.56 (s, 3H), 3.46 (s, 3H) and ¹H NMR (400 MHz, CDCl₃) δ 10.41 (s, 1H), 8.18 (d, J=3.2 Hz, 1H), 7.85 (d. J=3.1 Hz, 1H), 5.16 (s, 2H), 4.64-4.57 (m, 2H), 3.85-3.79 (m, J=5.4, 4.0 Hz, 2H), 3.50 (s, 3H), 3.46 (s, 3H); LRMS (M+H⁺) m/z 242.1.1

Step 5

To a solution of 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (1.27 g, 5.29 mol) in THF (5 mL) was added HCl (3 N, 4 mL). The reaction was stirred at 50° C. for 1 h, cooled to rt, and diluted with water (5 mL,). The mixture was neutralized to pH 7-8 with solid K₂CO₃ and the aqueous layer was extracted with EtOAc (100 mL) twice. The combined organic layers were dried over Na₂SO₄, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes to give 5-hydroxy-2-(2-methoxyethoxy)isonicotinaldehyde (630 mg, 60%) and 5-hydroxy-2-(2-methoxyethoxy)nicotinaldehyde (120 mg, 11%). Data for 5-hydroxy-2-(2-methoxyethoxy)isonicotinaldehyde: ¹H NMR (400 MHz, CDCl₃) δ 9.98 (s, 1H), 9.50 (s, 1H), 8.07 (s, 1H), 7.02 (s, 1H), 4.51-4.39 (m, 2H), 3.81-3.72 (m, 2H), 3.47 (s, 3H). LRMS (M+H⁺) m/z 198.1. Data for and 5-hydroxy-2-(2-methoxyethoxy)nicotinaldehyde: ¹H NMR (400 MHz, CDCl₃) δ 10.3 (s, 1H), 7.99 (d, J=3.2 Hz, 1H), 7.58 (d, J=3.2 Hz, 1H), 7.18-7.07 (br, 1H), 4.54 (dd, J=5.4, 3.7 Hz, 2H), 3.84 (dd, J=5.4, 3.7 Hz, 2H), 3.49 (s, 3H). LRMS (M+H⁺) m/z 198.1

Example 77 Preparation of 2-(2-methoxyethoxy)-5-((2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 184)

A mixture of 5-hydroxy-2-(2-methoxyethoxy)isonicotinaldehyde (125 mg, 0.63 mmol, 1 eq.), 3-(chloromethyl)-2-(1-methyl-1H-pyrazol-5-yl)pyridine hydrochloride salt (120 mg, 0.63 mmol, 1 eq.), and Cs₂CO₃ (410 mg, 1.26 mmol, 2 eq.) in DMF (3.0 mL) was heated at 60° C. for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-(2-methoxyethoxy)-5-((2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (59 mg, 25%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 10.22 (s, 1H), 8.59 (dd, J=4.7, 1.6 Hz, 1H), 7.87 (dd, J=7.9, 1.3 Hz, 1H), 7.73 (s, 1H), 7.38 (d, J=1.9 Hz, 1H), 7.27 (dd, J=7.9, 4.8 Hz, 1H), 7.00 (s, 1H), 6.25 (d, J=1.9 Hz, 1H), 5.02 (s, 2H), 4.26 (dd, J=5.4, 3.9 Hz, 2H), 3.80 (s, 3H), 3.57 (dd, J=5.4, 3.9 Hz, 2H), 3.28 (s, 3H). LRMS (M+H⁺) m/z 387.1.

Example 78 Preparation of 2-(2-methoxyethoxy)-5-((2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)nicotinaldehyde (Compound 185)

The title compound was prepared according to the procedure in Example 77.

¹H NMR (400 MHz, CDCl3) δ 10.38 (s, 1H), 8.74 (dd, J=4.7, 1.5 Hz, 1H), 8.07 (d, J=3.3 Hz, 1H), 7.98 (dd, J=7.9, 1.2 Hz, 1H), 7.64 (d, J=3.3 Hz, 1H), 7.53 (d, J=1.9 Hz, 1H), 7.41 (dd, J=7.9, 4.8 Hz, 1H), 6.41 (d, J=1.9 Hz, 1H), 5.04 (s, 2H), 4.62-4.51 (m, 2H), 3.96 (s, 3H), 3.82-3.76 (m, 2H), 3.45 (s, 3H).

Example 79 Preparation of 3-hydroxy-5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 186)

Step 1:

To a mixture of NaH (60% in mineral oil) (2.77 g, 69.25 mmol, 2.5 eq.) in DMF (40.0 mL) was added benzyl alcohol (6.6 g, 61.0 mmol, 2.2 eq.) at 0° C. The mixture was stirred at 0° C. for 10 min, added 3,5-dichloroisonicotinonitrile (4.8 g, 27.7 mmol, 1 eq.), continued to stir at 0° C. for 30 min, gradually warm to rt, stirred at rt O/N, and quenched with NH₄Cl_((sat.)) solution. The aqueous layer was extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na₂SO₄, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3,5-bis(benzyloxy)isonicotinonitrile (4.94 g, 56%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 2H), 7.58-7.30 (m, 10H), 5.33 (s, 4H). LRMS (M+H⁺) m/z 317.1

Step 2:

To a mixture of 3,5-bis(benzyloxy)isonicotinonitrile (2.5 g, 7.9 mmol, 1 eq.) and K₂CO₃ (4.37 g, 31.6 mmol, 4 eq.) in DMSO (10 mL) was added H₂O₂ (30% in water, 2.0 mL) at rt. The mixture was stirred at rt O/N and added water (50 mL). The solid was collected and dried to give 3,5-bis(benzyloxy)isonicotinamide (2.2 g, 83%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.13 (s, 2H), 7.59-7.33 (m, 10H), 5.83 (s, 2H), 5.25 (s, 4H), 4.81 (s, 2H). LRMS (M+H⁺) m/z 335.1

Step 3:

To 3,5-bis(benzyloxy)isonicotinamide (1.6 g, 4.79 mmol) in THF (30 mL) was added Cp2ZrCl (3.7 g, 14.4 mmol, 3 eq.) at rt. The mixture was stirred at rt for 2 h, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3,5-bis(benzyloxy)isonicotinaldehyde (580 mg, 38%) and (3,5-bis(benzyloxy)pyridin-4-yl)methanol (710 mg, 46%) as white solids. Data for aldehyde ¹H NMR (400 MHz, CDCl₃) δ 10.53 (s, 1H), 8.13 (s, 2H), 7.51-7.22 (m, 10H), 5.21 (s, 4H); LRMS (M+H⁺) m/z 320.1. Data for alcohol ¹H NMR (400 MHz, CDCl₃) δ 8.12 (s, 2H), 7.58-7.34 (m, 10H), 5.22 (s, 4H), 4.87 (s, 1H); LRMS (M+H) m/z 322.1.

Step 4:

To a solution of (3,5-bis(benzyloxy)pyridin-4-yl)methanol (910 mg, 2.83 mmol) and imidazole (385 mg, 5.66 mmol) in DMF (10.0 mL) was added TBSCl (513 mg, 3.4 mmol) at rt. The mixture was stirred at rt for 1 h and diluted with a mixture of water (10 mL) and EtOAc (40 mL). The organic layer was washed with NH₄Cl_((sat.)) solution and brine, dried over Na₂SO₄, concentrated, and purified on silica gel using 10% EtOAc/hexanes as eluent to give 3,5-bis(benzyloxy)-4-((tert-butyldimethylsilyloxy)methyl)pyridine (728 mg, 59%) as an off-white solid. LRMS (M+H⁺) m/z 436.3.

Step 5:

To 3,5-bis(benzyloxy)-4-((tert-butyldimethylsilyloxy)methyl)pyridine (720 mg, 1.66 mmol, 1 eq.) in a mixture of EtOAc/EtOH (5/2, 28 mL) was added Pd/C (400.0 mg). The mixture was charged with H₂ (60 psi), stirred at rt for 2 h, filtered, and concentrated to give 4-((tert-butyldimethylsilyloxy)methyl)pyridine-3,5-diol as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.54 (s, 21H), 4.91 (s, 21H), 0.73 (s, 9H), −0.00 (s, 6H). LRMS (M+H) m/z 256.1.

Step 6:

A mixture of 4-((tert-butyldimethylsilyloxy)methyl)pyridine-3,5-diol (100 mg, 0.39 mmol, 2 eq.) and Cs₂CO₃ (381 mg, 1.17 mmol, 3 eq.) in DMF (15 mL) was stirred at rt for 30 min. To this mixture was added 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride (53 mg, 0.39 mmol, 1 eq.) at it. The mixture was continued to stir at rt O/N, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 4-(hydroxymethyl)-5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)pyridin-3-ol (36 mg, 27%) as a pale yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.51 (dt, J=33.0, 16.5 Hz, 1H), 7.72 (d, J=1.6 Hz, 1H), 7.69 (s, 1H), 7.47 (s, 1H), 7.33 (s, 1H), 7.21 (dd, J=7.8, 4.8 Hz, 1H), 6.10 (d, J=1.8 Hz, 1H), 4.84 (s, 2H), 4.68 (s, 1H), 4.44 (sep, 6.6 Hz, 1H), 1.24 (d, J=6.6 Hz, 6H). LRMS (M+H⁺) m/z 341.1

Step 7:

To 4-(hydroxymethyl)-5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)pyridin-3-ol (26 mg, 0.076 mmol, 1 eq.) in CH₃CN (10 mL) was added MnO₂ (66 mg, 0.76 mmol, 10 eq.). The mixture was heated to 46° C. with stirring O/N, cooled to rt, filtered, and concentrated to give 3-hydroxy-5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde as a pale yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 11.06 (s, 1H), 10.35 (s, 1H), 8.70 (dd, J=4.7, 1.5 Hz, 1H), 8.11 (s, 1H), 7.89 (dd, J=7.9, 1.1 Hz, 1H), 7.80 (s, 1H), 7.53 (d, J=1.8 Hz, 1H), 7.36 (dd, J=7.9, 4.8 Hz, 1H), 6.27 (d, J=1.8 Hz, 1H), 5.14 (s, 2H), 4.61 (sep, J=6.6 Hz, 1H), 1.41 (d, J=6.6 Hz, 6H). LRMS (M+H⁺) m/z 339.1

Example 80 Preparation of 3-(benzyloxy)-5-hydroxyisonicotinaldehyde (Compound 187)

The title compound was prepared according to the procedure in Example 79.

¹H NMR (400 MHz, CDCl₃) δ 11.08 (s, 1H), 10.41 (s, 1H), 8.08 (s, 1H), 7.99 (s, 1H), 7.39-7.28 (m, 5H), 5.18 (s, 2H).

Example 81 Preparation of 3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-5-methoxyisonicotinaldehyde (Compound 188)

Step 1:

To a solution of 3,5-difluoropyridine (5.4 g, 46.8 mmol, 1 eq.) in MeOH (45 mL) was added NaOMe (7.5 g, 140.4 mmol). The mixture was divided into three microwave tubes and individually heated at 135° C. for 1 h in a microwave reactor. The three tubes were combined, concentrated, and diluted with a mixture EtOAc (100 mL) and brine (30 mL). The organic layer was dried over Na₂SO₄ and concentrated. The crude was re-dissolved in MeOH (45 mL) and added NaOMe (7.5 g, 140.4 mmol). The mixture was again divided into three microwave tubes and individually heated at 135° C. for 1 h in a microwave reactor. The three tubes were combined and concentrated. The crude was dissolved in a mixture of EtOAc (200 mL) and brine (30 mL). The organic layer was dried over Na₂SO₄, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3,5-dimethoxypyridine (3.73 g, 57%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.98 (d, J=2.4 Hz, 2H), 6.76 (t, J=2.4 Hz, 1H), 3.88 (s, 6H). LRMS (M+H⁺) m/z 140.1.

Step 2:

To a solution of 3,5-dimethoxypyridine (3.6 g, 25.90 mmol, 1 eq.) in THF (80 mL) was added BuLi (3M/hexanes, 13.0 mL, 38.85 mmol, 1.5 eq.) at −20° C. The mixture was warmed to 0° C., stirred at 0° C. for 30 min, cooled back down to −78° C., and added DMF (3.8 g, 51.8 mmol, 2 eq.). The mixture was gradually warmed to 0° C., quenched with NH₄Cl_((sat.)) solution, and diluted with EtOAc. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na₂SO₄, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3,5-dimethoxyisonicotinaldehyde (2.7 g, 62%) as a yellow solid. LRMS (M+H⁺) m/z 168.1.

Step 3:

To a solution of 3,5-dimethoxyisonicotinaldehyde (2.7 g, 16.16 mmol, 1 eq.) in DCM (100 mL) was added AlCl₃ (4.31 g, 32.32 mmol, 2.0 eq.) at rt. The mixture was reflux O/N, cooled to rt, and added into ice (200 g). The aqueous layer was extracted with DCM three times. The combined organic layers were dried over Na₂SO₄, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3-hydroxy-5-methoxyisonicotinaldehyde (420 mg, 17%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 10.96 (s, 1H), 10.26 (s, 1H), 7.96 (s, 1H), 7.80 (s, 1H), 3.84 (s, 3H). LRMS (M+H⁺) m/z 154.1.

Step 4:

A mixture of 3-hydroxy-5-methoxyisonicotinaldehyde (30 mg, 0.20 mmol, 1 eq.), 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride (54 mg, 0.20 mmol, 1 eq.), and K₂CO₃ (110 mg, 0.80 mmol, 4 eq.) in DMF (2.0 mL) was heated at 70° C. for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes to give 3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-5-methoxyisonicotinaldehyde (30 mg, 43%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 10.46 (s, 1H), 8.65 (dd, J=4.7, 1.1 Hz, 1H), 8.13 (s, 1H), 8.11 (dd, J=7.9, 1.1 Hz, 1H), 7.96 (s, 1H), 7.54 (d, J=1.7 Hz, 1H), 7.37 (dd, J=7.9, 4.8 Hz, 1H), 6.29 (d, J=1.7 Hz, 1H), 5.11 (s, 2H), 4.55 (sep, J=6.6 Hz, 1H), 3.95 (s, 3H), 1.40 (d, J=6.6 Hz, 6H). LRMS (M+H⁺⁾ m/z 353.1.

Example 82 Preparation of 5-((2-(2-isopropyl-2H-1,2,4-triazol-3-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (Compound 189)

Step 1:

To 5-hydroxy-2-methoxyisonicotinaldehyde (1.0 g, 6.54 mmol, 1.0 eq.) in toluene (50.0 mL) were added ethane-1,2-diol (10.0 mL) and PTSA (248 mg, 1.31 mmol, 0.2 eq.). The mixture was heated to reflux O/N, cooled to rt, neutralized to pH 8, and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated to give 4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-ol (980 mg, 76%) as an off-white solid. LRMS (M+H⁺) m/z 198.1.

Step 2:

A mixture of 4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-ol (980 mg, 4.97 mmol, 1 eq.), 2-bromo-3-(chloromethyl)pyridine hydrochloride (1.2 g, 4.93 mmol, 1 eq.) and K₂CO₃ (2.7 g, 19.88 mmol, 4 eq.) in DMF (10.0 mL) was heated at 70° C. for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 5-((2-bromopyridin-3-yl)methoxy)-4-(1,3-dioxolan-2-yl)-2-methoxypyridine (1.21 g, 66%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.26 (dd, J=4.7, 1.9 Hz, 1H), 7.83 (dd, J=7.6, 1.9 Hz, 1H), 7.74 (s, 1H), 7.25 (dd, J=7.6, 4.8 Hz, 1H), 6.86 (s, 11H), 6.10 (s, 1H), 5.09 (s, 2H), 4.07-3.93 (m, 4H), 3.82 (s, 3H). LRMS (M+H⁺) m/z 367.0.

Step 3:

A mixture of 5-((2-bromopyridin-3-yl)methoxy)-4-(1,3-dioxolan-2-yl)-2-methoxypyridine (1.1 g, 3.0 mmol, 1 eq.), Zn (CN)₂ (704 mg, 6.0 mmol, 2.0 eq.), and Pd(PPh₃)₄ (346 mg, 0.3 mmol, 0.2 eq.) in DMF (10 mL) was heated at 125° C. for 2 h under N₂. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)picolinonitrile (820 mg, 84%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.71 (d, J=4.6 Hz, 1H), 8.12 (dd, J=8.0, 0.7 Hz, 1H), 7.88 (s, 1H), 7.60 (dd, J=8.0, 4.7 Hz, 1H), 6.95 (s, 1H), 6.16 (s, 1H), 5.37 (s, 2H), 4.18-4.00 (m, 4H), 3.92 (s, 3H). LRMS (M+H⁺) m/z 314.1.

Step 4:

To 3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)picolinonitrile (150 mg, 0.48 mmol, 1 eq.) in a mixture of EtOH/water (5/1, 12 mL) was added NaOH (192 mg, 4.8 mmol, 10 eq.). The mixture was heated to reflux O/N, partially concentrated, added ice, and acidified to pH 3 with HCl_((conc.)). The solid was collected and dried to give 3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)picolinic acid (145 mg, 91%) as a white solid. ¹H NMR (400 MHz, MeOD) δ 8.38-8.48 (br, 1H), 8.28-8.35 (br, 1H), 7.76 (s, 1H), 7.50-7.70 (br, 1H), 6.81 (s, 1H), 6.04 (s, 1H), 5.50-5.64 (br, 2H), 4.03-3.87 (m, 3H), 3.75 (s, 3H). LRMS (M+H⁺) m/z 333.0.

Step 5:

To a mixture of 3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)picolinic acid (145 mg, 0.44 mmol, 1 eq.) and EDCI.HCl (169 mg, 0.88 mmol, 2 eq.) in DMF (3.0 mL) was added DIEA (146 uL, 0.88 mmol, 2 eq.). The mixture was stirred at rt for 1 h and purified by RP-HPLC (Gemini 21.2×150 mm) using a mixture of CH₃CN and water to isolate the urea intermediate. The fractions were concentrated and dissolved in EtOH (5.0 mL). To this mixture was added hydrazine (0.5 mL) at rt. The mixture was stirred at rt for 1 h, partially concentrated, and diluted with water (10 mL). The solid was collected, washed with water, and dried to give 3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)picolinohydrazide (97 mg, 64% for two steps) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 9.13 (s, 1H), 8.51 (d, J=4.6 Hz, 1H), 8.24 (d, J=7.9 Hz, 1H), 7.85 (s, 1H), 7.51 (dd, J=8.0, 4.6 Hz, 1H), 6.95 (s, 1H), 6.24 (s, 1H), 5.80 (s, 2H), 4.20-4.06 (m, 4H), 3.90 (s, 3H). LRMS (M+H⁺) m/z 347.1.

Step 6:

To a mixture of 3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)picolinohydrazide (90 mg, 0.26 mmol, 1 eq.) and AcOH (0.4 mL) in dioxane (2.0 mL) was added CH(OMe)₃ (0.4 mL). The mixture was sealed and heated at 110° C. for 1 h, cooled to rt, and added isopropyl amine (0.4 mL). The mixture was re-sealed, heated at 110° C. O/N, concentrated, and purified on RP-HPLC (Gemini 21.2×150 mm) using a mixture of CH₃CN and water as eluent to give 4-(1,3-dioxolan-2-yl)-5-((2-(2-isopropyl-2H-1,2,4-triazol-3-yl)pyridin-3-yl)methoxy)-2-methoxypyridine (68 mg, 66%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.66 (dd, J=4.7, 1.2 Hz, 1H), 8.41 (s, 1H), 8.24 (dd, J=8.0, 1.2 Hz, 1H), 7.76 (s, 1H), 7.45 (dd, J=8.0, 4.7 Hz, 1H), 6.90 (s, 1H), 6.17 (s, 1H), 5.61 (s, 2H), 5.30 (sep, J=6.7 Hz, 1H), 4.17-4.02 (m, 4H), 3.88 (s, 3H), 1.55 (d, J=6.7 Hz, 6H). LRMS (M+H⁺) m/z 398.2.

Step 7:

To 4-(1,3-dioxolan-2-yl)-5-((2-(2-isopropyl-2H-1,2,4-triazol-3-yl)pyridin-3-yl)methoxy)-2-methoxypyridine (60 mg, 0.15 mmol, 1 eq.) in a RB flask was added HCl (6 N, 2.0 mL). The mixture was warmed to 40° C. O/N, cooled to rt, neutralized to pH 7-8 with NaHCO_(3(sat)) solution, and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated to give 5-((2-(2-isopropyl-2H-1,2,4-triazol-3-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (52.2 mg, 99%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 10.35 (s, 1H), 8.62 (dd, J=4.6, 1.2 Hz, 1H), 8.33 (s, 1H), 8.11 (dd, J=8.0, 1.2 Hz, 1H), 7.98 (s, 1H), 7.40 (dd, J=8.0, 4.7 Hz, 1H), 6.99 (s, 1H), 5.62 (s, 2H), 5.28 (sep, J=6.7 Hz, 1H), 3.82 (s, 3H), 1.46 (d, J=6.7 Hz, 6H). LRMS (M+H⁺) m/z 354.1.

Example 83 Preparation of 5-((2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (Compound 190)

Step 1:

Ethylmagnesium bromide (3M/ether, 1.53 mL, 4.60 mmol, 1.5 eq.) was added to a stirred solution of 3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)picolinonitrile (960 mg, 3.07 mmol, 1 eq.) in THF (15.0 mL) at −78° C. After addition, the reaction mixture was allowed to warm to rt and quenched with aqueous citric acid solution. The aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layers were washed with NaHCO_(3 (sat)) solution and brine, dried over Na₂SO₄, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 1-(3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)propan-1-one (611 mg, 58%) as a colorless oil. LRMS (M+H⁺) m/z 345.1.

Step 2:

1-(3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)propan-1-one (600 mg, 1.74 mmol) in dimethoxy-N,N-dimethylmethanamine (10.0 mL) was heated to reflux O/N. The mixture was concentrated to give (E)-1-(3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-3-(dimethylamino)-2-methylprop-2-en-1-one, which was used for next step without further purification. LRMS (M+H⁺) m/z 400.2.

Step 3:

To (E)-1-(3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-3-(dimethylamino)-2-methylprop-2-en-1-one (crude, 230 mg, 0.58 mmol, 1 eq.) in EtOH (5 mL) was added isopropylhydrazine hydrochloride (128 mg, 1.16 mmol, 2 eq.) at rt. The mixture was heated at 80° C. for 2 h, cooled to rt, concentrated, and diluted with a mixture of EtOAc (50 mL) and NaHCO_(3 (sat)) (10.0 mL) solution. The layers were separated and aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na₂SO₄, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 4-(1,3-dioxolan-2-yl)-5-((2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxypyridine (48 mg, 20% for two steps). ¹H NMR (400 MHz, CDCl₃) δ 8.75 (dd, J=4.7, 1.4 Hz, 1H), 8.12 (d, J=8.1 Hz, 1H), 7.62 (s, 1H), 7.49-7.44 (m, 2H), 6.91 (s, 1H), 6.11 (s, 1H), 4.85-5.01 (m, 2H), 4.30-3.98 (m, 5H), 3.88 (s, 3H), 1.94 (s, 3H), 1.50 (d, J=6.7 Hz, 3H), 1.39 (d, J=6.7 Hz, 3H). LRMS (M+H⁺) m/z 411.2.

Step 4:

To 4-(1,3-dioxolan-2-yl)-5-((2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxypyridine (41 mg, 0.1 mmol, 1 eq.) in a RB flask was added HCl (6 N, 2.0 mL). The mixture was warmed to 40° C. O/N, cooled to rt, neutralized to pH 7-8 with NaHCO_(3(sat)) solution, and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na₂SO₄, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 5-((2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (33.3 mg, 99%) as an pale-yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 10.32 (s, 1H), 8.71 (dd, J=4.7, 1.6 Hz, 1H), 7.99 (dd, J=7.9, 1.5 Hz, 1H), 7.76 (s, 1H), 7.40 (dd, J=7.1, 4.7 Hz, 1H), 7.39 (s, 1H), 7.01 (s, 1H), 4.86-4.99 (m, 2H), 4.12 (sep, J=6.7, 1H), 3.82 (s, 3H), 1.86 (s, 3H), 1.40 (d, J=767 Hz, 3H), 1.29 (d, J=6.7 Hz, 3H). LRMS (M+H⁺) m/z 367.1.

Example 84 Preparation of 5-((2-(1-(2-hydroxyethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (Compound 191)

The title compound was prepared according to the procedure in Example 83.

¹H NMR (400 MHz, CDCl₃) δ 10.18 (s, 1H), 8.50 (dd, J=4.8, 1.6 Hz, 1H), 7.89 (dd, J=7.9, 1.5 Hz, 1H), 7.72 (s, 1H), 7.42 (d, J=1.9 Hz, 1H), 7.27 (dd, J=7.9, 4.9 Hz, 1H), 6.90 (s, 1H), 6.26 (d, J=1.9 Hz, 1H), 5.34 (s, 1H), 5.04 (s, 2H), 4.24-4.16 (m, 2H), 3.94-3.85 (m, 2H), 3.70 (s, 3H).

Example 85 Synthesis of 2,2,2-trifluoroacetic acid:6-(((4-formylpyridin-3-yl)oxy)methyl)picolinic acid (1:1) (Compound 192)

Step 1:

Into a 25-mL round-bottom flask, was placed a solution of pyridine-2,6-dicarboxylic acid (1 g, 5.98 mmol, 1.00 equiv) in methanol (12.5 mL). Sulfuric acid (2.5 mL) was added to the reaction mixture. The resulting solution was stirred overnight at 70° C., and then it was quenched by the addition of 10 mL of water. The pH value of the solution was adjusted to 7 with sodium carbonate. The resulting solution was extracted with 2×25 mL of dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.95 g (81%) of 2,6-dimethyl pyridine-2,6-dicarboxylate as a white solid

Step 2:

Into a 100-mL round-bottom flask, was placed a solution of 2,6-dimethyl pyridine-2,6-dicarboxylate (950 mg, 4.87 mmol, 1.00 equiv) in a solvent mixture of methanol (33.2 mL) and dichloromethane (14.2 mL). NaBH₄ (185 mg, 5.02 mmol, 1.00 equiv) was added to the reaction mixture in several batches at 0° C. The resulting solution was stirred overnight at room temperature, and then it was quenched by the addition of 50 mL of NH₄Cl (aq.). The resulting solution was extracted with 2×50 mL of dichloromethane and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1-2:1) as eluent to yield 750 mg (92%) of methyl 6-(hydroxymethyl)pyridine-2-carboxylate as a white solid.

Step 3:

Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 6-(hydroxymethyl)pyridine-2-carboxylate (300 mg, 1.79 mmol, 1.00 equiv) in tetrahydrofuran (15 mL). 4-(Dimethoxymethyl)pyridin-3-ol (304.2 mg, 1.80 mmol, 1.00 equiv), and triphenylphosphane (615 mg, 2.34 mmol, 1.30 equiv) was added to the reaction mixture. This was followed by the addition of DIAD (473.1 mg, 2.34 mmol, 1.30 equiv) dropwise at 0° C. The resulting solution was stirred overnight at room temperature, and then it was quenched by the addition of 10 mL of water. The resulting solution was extracted with 2×50 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5-1:1) as eluent to yield 340 mg (60%) of methyl 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-2-carboxylate as a white solid.

Step 4:

Into a 100-mL round-bottom flask, was placed methyl 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-2-carboxylate (310 mg, 0.97 mmol, 1.00 equiv) and sodium hydroxide (117 mg, 2.93 mmol, 3.00 equiv) in a solvent mixture of methanol (10 mL), water (10 mL) and tetrahydrofuran (10 mL). The resulting solution was stirred overnight at room temperature. The pH value of the solution was adjusted to 4-5 with hydrogen chloride (1 mol/L). The resulting solution was extracted with 3×20 mL of isopropal/DCM (1/3) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 230 mg (78%) of 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-2-carboxylic acid as a white solid.

Step 5:

Into an 8-mL scaled tube, was placed a solution of 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-2-carboxylic acid (150 mg, 0.49 mmol, 1.00 equiv) in dichloromethane (4 mL) and trifluoroacetic acid (2 mL). The resulting solution was stirred for 3.5 h at 45° C. in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and MeCN (10% MeCN up to 35% in 4 min, up to 100% in 1 min, down to 10% in 1 min); Detector, Waters2545 UvDector 254&220 nm. This resulted in 49 mg (38%) of 6-[[(4-formylpyridin-3-yl)oxy]methyl]pyridine-2-carboxylic acid as a light yellow solid. LC-MS-PH-GBT-ZL-HS-19-0 (ES, m/z): 259 [M+1]⁺ H-NMR-PH-GBT-ZL-HS-19-0 (300 MHz, DMSO, ppm): 10.52 (s, 1H), 8.92 (s, 1H), 8.52 (d, J=4.8 Hz, 1H), 8.09 (m, 2H), 7.95 (m, 1H), 7.76 (d, J=4.8 Hz, 1H), 5.61 (s, 2H).

Example 86 Preparation of 5-((2-(4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-oxo-1,2-dihydropyridine-4-carbaldehyde (Compound 194)

To 2-methoxy-5-((2-(4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (862 mg, 2.66 mmol, 1 equiv) suspended in water (5.0 mL) was added HCl (6 N, 4.43 mL, 26.6 mmol, 10 eq.). Once the mixture turned into a homogeneous solution, it was freeze at −78° C. to an solid and pump under high vacuum O/N. The yellow solid was continued to pump at 45° C. for 20 h, dissolved in water (2.0 mL), and basified to pH 11 with NaOH (2 N). The aqueous layer was washed with DCM three times and the pH of the mixture was adjusted to pH 6-7. The solid was collected and dried to give 5-((2-(4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-oxo-1,2-dihydropyridine-4-carbaldehyde (180 mg, 44% based on 50% recovered of SM) as a white solid. ¹H NMR (400 MHz, DMSO at 90° C.) δ 10.14 (s, 1H), 8.63 (s, 1H), 8.09-8.03 (br, 1H), 7.56-7.50 (br, 2H), 7.42-7.35 (br, 1H), 6.70 (s, 1H), 5.39 (s, 2H), 2.18 (s, 3H). LRMS (M+H⁺) m/z 311.1.

Example 87 Preparation of 2-(5-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetic acid (Compound 199)

Step 1

To (E)-1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-3-(dimethylamino)prop-2-en-1-one (crude, 350 mg, 1.09 mmol, 1 eq.) in EtOH (10 mL) was added ethyl 2-hydrazinylacetate hydrochloride (338 mg, 2.18 mmol, 2.0 eq.). The mixture was heated at 80° C. for 2 h, cooled to rt, added HCl (6 N, 0.5 mL), and stirred O/N. The mixture was concentrated, and diluted with a mixture of EtOAc (50 mL) and NaHCO_(3(sat)) (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na₂SO₄, concentrated, and purified on silica gel using EtOAc as eluent to give ethyl 2-(5-(3-(hydroxymethyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetate (212 mg, 74%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 8.61 (dd, J=4.7, 1.6 Hz, 1H), 7.97 (dd, J=7.8, 1.4 Hz, 1H), 7.64 (d, J=1.9 Hz, 1H), 7.36 (dd, J=7.8, 4.8 Hz, 1H), 6.56 (d, J=1.9 Hz, 1H), 5.21 (s, 2H), 4.79 (d, J=5.8 Hz, 2H), 4.09 (q, J=7.1 Hz, 2H), 2.54 (t, J=6.0 Hz, 1H), 1.18 (t, J=7.1 Hz, 3H). LRMS (M+H⁺) m/z 262.1

Step 2

To ethyl 2-(5-(3-(hydroxymethyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetate (182 mg, 0.70 mmol) in DCM (10 mL) was added SOCl₂ (3.0 mL) at rt. The reaction mixture was stirred at rt for 4 h and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give ethyl 2-(5-(3-(chloromethyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetate hydrochloride (220 mg) as an off-white solid, which was used for next step without further purification.

Step 3

A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (107 mg, 0.70 mmol, 1 eq.), ethyl 2-(5-(3-(chloromethyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetate hydrochloride (220 mg, 0.70 mmol, 1 eq.), and K₂CO₃ (386 mg, 2.8 mmol, 4 eq.) in DMF (6.0 mL) was heated at 70° C. for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give ethyl 2-(5-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetate (261 mg, 94%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 10.45 (s, 1H), 8.69 (d, J=3.8 Hz, 1H), 8.02 (s, 1H), 8.01 (d, J=7.5 Hz, 1H), 7.63 (d, J=1.6 Hz, 1H), 7.40 (dd, J=7.6, 4.0 Hz, 1H), 7.13 (s, 1H), 6.53 (d, J=1.6 Hz, 1H), 5.30 (s, 2 H), 5.28 (s, 2H), 4.12 (q, J=7.1 Hz, 2H), 3.93 (s, 3H), 1.18 (t, J=7.1 Hz, 3H). LRMS (M+H⁺) m/z 397.1.

Step 4

To ethyl 2-(5-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetate (182 mg, 0.46 mmol, 1 eq.) in a mixture of MeOH/THF (1/5, 12.0 mL) was added NaOH (2N, 2.3 mL, 4.6 mmol, 10 eq.). The mixture was stirred at rt for 2 h, acidified to pH 3, and extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na₂SO₄ and concentrated to give 2-(5-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetic acid (135.1 mg, 80%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 10.42 (s, 1H), 8.71 (d, J=4.7 Hz, 1H), 8.13 (d, J=7.8 Hz, 1H), 7.97 (s, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.52 (dd, J=7.9, 4.9 Hz, 1H), 7.13 (s, 1H), 6.56 (d, J=1.7 Hz, 1H), 5.31 (s, 2H), 5.14 (s, 2H), 3.91 (s, 3H). LRMS (M+H⁺) m/z 369.1.

Examples 88 and 89 were prepared according to example 87 above.

Example 88 Preparation of methyl 3-(5-(3-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate (Compound 200)

¹H NMR (400 MHz, CDCl3) δ 10.44 (s, 1H), 8.75 (dd, J=4.8, 1.6 Hz, 1H), 8.05 (dd, J=7.9, 1.4 Hz, 1H), 7.99 (s, 1H), 7.58 (d, J=1.9 Hz, 1H), 7.44 (dd, J=7.9, 4.8 Hz, 1H), 7.12 (s, 1H), 6.41 (d, J=1.9 Hz, 1H), 5.21 (s, 2H), 4.55 (t, J=7.1 Hz, 2H), 3.92 (s, 3H), 3.62 (s, 3H), 3.00 (t, J=7.1 Hz, 2H).

Example 89 Preparation of 3-(5-(3-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoic acid (Compound 202)

¹H NMR (400 MHz, CDCl3) δ 10.33 (s, 1H), 8.66 (dd, J=4.8, 1.6 Hz, 1H), 7.96 (dd, J=7.9, 1.5 Hz, 1H), 7.83 (s, 1H), 7.53 (d, J=1.9 Hz, 1H), 7.37 (dd, J=7.9, 4.8 Hz, 1H), 7.02 (s, 1H), 6.33 (d, J=1.9 Hz, 1H), 5.13 (s, 2H), 4.49 (t, J=6.5 Hz, 2H), 3.81 (s, 3H), 2.94 (t, J=6.5 Hz, 2H).

Example 90 Preparation of 3-(3-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoic acid (Compound 201)

Step 1

To (E)-1-(3-((tert-butyldimethylsiloxy)methyl)pyridin-2-yl)-3-(dimethylamino)prop-2-en-1-one (crude, 350 mg, 1.09 mmol, 1 eq.) in EtOH (5 mL) was added hydrazine (140 mg, 4.36 mmol, 4 eq.). The mixture was heated at 80° C. for 2 h, cooled, concentrated, and purified on silica gel using EtOAc as eluent to give 3-((tert-butyldimethylsilyloxy)methyl)-2-(1H-pyrazol-5-yl)pyridine (282 mg, 90%) as a white solid. LRMS (M+H⁺) m/z 290.1

Step 2

To a mixture of 3-((tert-butyldimethylsilyloxy)methyl)-2-(1H-pyrazol-5-yl)pyridine (140 mg, 0.48 mmol, 1 eq.) and Cs₂CO₃ (312 mg, 0.96 mmol, 2 eq.) in DMF (3 mL) was added methyl 3-bromopropanoate (122 mg, 0.73 mmol, 1.5 eq.). The mixture was stirred at rt for 6 h, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give methyl 3-(3-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate (110 mg, 61%). LRMS (M+H⁺) m/z 376.1.

Step 3

To methyl 3-(3-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate in MeOH (10 mL) was added HCl (2 N, 1.2 mL, 10 eq.). The mixture was stirred at rt for 4 h, concentrated, neutralized to pH 7-8 with NaHCO_(3(sat)) solution, and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na₂SO₄, concentrated, and purified on silica gel using EtOAc as eluent to give methyl 3-(3-(3-(hydroxymethyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate (51 mg, 67%) as an oil. LRMS (M+H⁺) m/z 262.1.

Step 4

To methyl 3-(3-(3-(hydroxymethyl)pyridin-2-yl)-1-H-pyrazol-1-yl)propanoate (51 mg, 0.20 mmol) in DCM (5 mL) was added SOCl₂ (1.0 mL) at rt. The reaction mixture was stirred at rt for 4 h and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give methyl 3-(3-(3-(chloromethyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate hydrochloride (63 mg) as an off-white solid, which was used for next step without further purification.

Step 5

A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (30 mg, 0.20 mmol, 1 eq.), methyl 3-(3-(3-(chloromethyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate hydrochloride (63 mg, 0.20 mmol, 1 eq.), and K₂CO₃ (100 mg, 10.32 mmol, 4 eq.) in DMF (5.0 mL) was heated at 70° C. for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give methyl 3-(3-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate (88 mg, quantitative yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 10.50 (s, 1H), 8.65 (dd, J=4.7, 0.9 Hz, 1H), 8.09 (s, 1H), 8.02 (dd, J=7.8, 0.8 Hz, 1H), 7.53 (d, J=2.3 Hz, 1H), 7.31 (dd, J=7.9, 4.8 Hz, 1H), 7.12 (s, 1H), 6.96 (d, J=2.3 Hz, 1H), 5.71 (s, 2H), 4.46 (t, J=6.6 Hz, 2H), 3.93 (s, 3H), 3.69 (s, 3H), 2.91 (t, J=6.6 Hz, 2H). LRMS (M+H⁺) m/z 397.1.

Step 6

To methyl 3-(3-(3-((4-formyl-6-methoxypyridin-3-yloxy)methylpyridin-2-yl)-1H-pyrazol-1-yl)propanoate (72 mg, 0.18 mmol, 1 eq.) in a mixture of MeOH/THF (1/6, 6.0 mL) was added NaOH (3 N, 0.6 mL, 1.8 mmol, 10 eq.). The mixture was stirred at rt for 2 h, acidified to pH 3, extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na₂SO₄ and concentrated to give 3-(3-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoic acid (53.4 mg, 78%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 10.42 (s, 1H), 8.57 (d, J=4.6 Hz, 1H), 8.08 (s, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.46 (d, J=2.3 Hz, 1H), 7.23 (dd, J=7.9, 4.6 Hz, 1H), 7.03 (s, 1H), 6.85 (d, J=2.3 Hz, 1H), 5.64 (s, 2H), 4.42 (t, J=6.1 Hz, 2H), 3.83 (s, 3H), 2.86 (t, J=6.1 Hz, 2H). LRMS (M+H⁺) m/z 383.1.

Example 91 Preparation of 6-(((4-formylpyridin-3-yl)oxy)methyl)nicotinonitrile 2,2,2-trifluoroacetate (Compound 204)

Step 1:

Into a 250-mL round-bottom flask, was placed a solution of 6-methylpyridine-3-carbonitrile (8 g, 67.72 mmol, 1.00 equiv) in CCl4 (125 mL). N-Bromosuccinimide (13.4 g, 75.29 mmol, 1.10 equiv), and AIBN (480 mg, 2.92 mmol, 0.04 equiv) were added to the reaction solution. The resulting solution was stirred for 5 h at 85° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) as eluent to yield 5 g (37%) of 6-(bromomethyl)pyridine-3-carbonitrile as a beige solid.

Step 2:

Into a 250-mL round-bottom flask, was placed a solution of 6-(bromomethyl)pyridine-3-carbonitrile (3 g, 15.23 mmol, 1.00 equiv) in CH3CN (100 mL). Potassium carbonate (4.24 g, 30.68 mmol, 2.00 equiv) and 4-(dimethoxymethyl)pyridin-3-ol (2.83 g, 16.73 mmol, 1.10 equiv) were added to the reaction mixture. The resulting solution was stirred for 2 h at 50° C., and then it was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3) as eluent to furnish 1.4 g (32%) of 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-3-carbonitrile as a red solid.

Step 2:

Into an 8-mL vial, was placed a solution of 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-3-carbonitrile (100 mg, 0.35 mmol, 1.00 equiv) in a mixture of dichloromethane (2 mL) and trifluoroacetic acid (1 mL). The resulting solution was stirred for 5 h at 45° C., and then it was concentrated under vacuum. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water and MeCN (10.0% MeCN up to 40.0% in 3 min, up to 100.0% in 2 min, down to 10.0% in 1 min); Detector, Waters2545 UvDector 254&220 nm. This resulted in 8 mg (10%) of 6-[[(4-formylpyridin-3-yl)oxy]methyl]pyridine-3-carbonitrile as a white solid. LC-MS-PH-GBT-ZL-HS-13-0: (ES, m/z):258 [M+1+18]⁺. H-NMR-PH-GBT-ZL-HS-13-0: (300 MHz, DMSO, ppm): 10.48 (s, 1H), 9.06 (s, 1H), 8.80 (s, 1H), 8.47 (m, 2H), 7.94 (d, J=8.1 Hz, 1H), 7.65 (d, J=5.1 Hz, 1H), 5.69 (s, 2H).

Example 92 Preparation of 6-(((4-formylpyridin-3-yl)oxy)methyl)nicotinic acid hydrochloride (Compound 205)

Step 1:

Into a 100-mL round-bottom flask, was placed a solution of 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-3-carbonitrile (1 g, 3.51 mmol, 1.00 equiv) in water (30 mL). Sodium hydroxide (1.4 g, 35.00 mmol, 10.00 equiv) was added to the reaction. The resulting solution was stirred for 4 h at 90° C. The pH value of the solution was adjusted to 4-5 with hydrogen chloride (aq. 3 mol/L). The resulting solution was extracted with 3×200 ml of ethyl acetate. The aqueous layer was extracted again with 3×200 ml of tetrahydrofuran. The combined organic layers were concentrated under vacuum. This resulted in 1 g (94%) of 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-3-carboxylic acid as a yellow solid.

Step 2:

Into an 8-mL vial, was placed a solution of 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-3-carboxylic acid (100 mg, 0.33 mmol, 1.00 equiv) in a solvent mixture of dichloromethane (2 mL) and trifluoroacetic acid (1 mL). The resulting solution was stirred for 3 h at 40° C., and then it was concentrated under vacuum. The crude product (70 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water (0.05% HCl) and MeCN (10.0% MeCN up to 40.0% in 3 min, up to 100.0% in 2 min, down to 10.0% in 1 min); Detector, Waters2545 UvDector 254&220 nm. This resulted in 30 mg (31%) of 6-[[(4-formylpyridin-3-yl)oxy]methyl]pyridine-3-carboxylic acid hydrochloride as a white solid. The compound exhibited a melting point of 192-194° C. LC-MS-PH-GBT-ZL-HS-14-0: (ES, m/z):259 [M+1]+/277 [M+1+18]⁺. H-NMR-PH-GBT-ZL-HS-14-0: (300 MHz, DMSO, ppm): 13.42 (s, 1H), 10.48 (s, 1H), 9.03 (s, 1H), 8.74 (s, 1H), 8.40 (d, J=4.8 Hz, 1H), 8.30 (dd, J=8.1 Hz, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.57 (d, J=4.8 Hz, 1H), 5.55 (s, 2H).

Example 93 Preparation of 2,2,2-trifluoroacetic acid:6-(((4-formylpyridin-3-yl)oxy)methyl)-N-(methylsulfonyl)nicotinamide (2:1) (Compound 206)

Step 1:

Into a 100-mL round-bottom flask, was placed a solution of 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-3-carbonitrile (1 g, 3.51 mmol, 1.00 equiv) and sodium hydroxide (1.4 g, 35.00 mmol, 10.00 equiv) in water (30 mL). The resulting solution was stirred for 4 h at 90° C. The pH value of the solution was adjusted to 4-5 with hydrogen chloride (3 mol/L). The resulting solution was extracted with 3×200 mL of ethyl acetate and 3×200 ml of tetrahydrofuran. The combined organic layers were concentrated under vacuum. This resulted in 1 g (94%) of 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-3-carboxylic acid as a yellow solid.

Step 2.

Into a 100-mL round-bottom flask, was placed a solution of 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-3-carboxylic acid (200 mg, 0.66 mmol, 1.00 equiv) in dichloromethane (30 mL). EDCI (190 mg, 0.99 mmol, 1.50 equiv), 4-dimethylaminopyridine (120 mg, 0.98 mmol, 1.50 equiv), and methanesulfonamide (80 mg, 0.84 mmol, 1.20 equiv) were added to the reaction mixture. The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with MeOH:DCM (1:10) as eluent. This resulted in 200 mg (80%) of 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)-N-methanesulfonylpyridine-3-carboxamide as a yellow solid.

Step 3:

Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)-N-methanesulfonylpyridine-3-carboxamide (80 mg, 0.21 mmol, 1.00 equiv) in dichloromethane (5 mL), and trifluoroacetic acid (2 mL). The resulting solution was stirred for 3 h at 40° C. in an oil bath, and then it was concentrated under vacuum. The crude product (60 mg) was purified by Flash-Prep-HPLC with the following conditions (CombiFlash-1): Column, C18 silica gel; mobile phase, CH₃CN/H₂O=1/99 increasing to CH₃CN/H₂O=40/60 within 20 min; Detector, UV 254 nm. This resulted in 20 mg (17%) of 6-[[(4-formylpyridin-3-yl)oxy]methyl]-N-methanesulfonylpyridine-3-carboxamide; bis(trifluoroacetic acid) as a white solid. The compound exhibited a melting point of 102-104° C. LC-MS: (ES, m/z):336 [M+1]+/354 [M+1+8]⁺. H-NMR (300 MHz, DMSO, ppm): 10.53 (s, 1H), 9.07 (s, 1H), 8.78 (s, 1H), 8.43 (d, J=4.5 Hz, 1H), 8.36 (dd, J=8.1 Hz, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.62 (d, J=4.5 Hz, 1H), 5.60 (s, 2H), 3.37 (s, 3H).

Example 94 Preparation of Substituted Isonicotinaldehydes

Compounds 207-217 were prepared according to the methods described above.

2-(2-methoxyethoxy)-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 207). ¹H NMR (400 MHz, CDCl₃) δ 10.32 (s, 1H), 8.67 (dd, J=4.8, 1.6 Hz, 1H), 7.97 (dd, J=7.9, 1.5 Hz, 1H), 7.87 (s, 1H), 7.59 (d, J=1.9 Hz, 1H), 7.38 (dd, J=7.9, 4.8 Hz, 1H), 7.11 (s, 1H), 6.47 (d, J=1.9 Hz, 1), 5.17 (q, J=8.6 Hz, 2H), 5.10 (s, 2H), 4.39-4.32 (m, 2H), 3.70-3.63 (m, 2H), 3.37 (s, 3H).

2-methoxy-5-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 208). ¹H NMR (400 MHz, CDCl₃) δ 10.41 (s, 1H), 8.77 (dd, J=4.7, 1.6 Hz, 1H), 8.06 (dd, J=7.9, 1.6 Hz, 1H), 7.97 (s, 1H), 7.61 (d, J=1.9 Hz, 1H), 7.46 (dd, J=7.9, 4.8 Hz, 1H), 7.13 (s, 1H), 6.46 (d, J=1.9 Hz, 1H), 5.21 (s, 2H), 4.61-4.49 (m, 2H), 3.93 (s, 3H), 2.95-2.79 (m, 2H).

2-(2-methoxyethoxy)-5-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 209). ¹H NMR (400 MHz, CDCl₃) δ 10.40 (s, 1H), 8.76 (dd, J=4.7, 1.6 Hz, 1H), 8.06 (dd, J=7.9, 1.6 Hz, 1H), 7.93 (s, 1H), 7.61 (d, J=1.9 Hz, 1H), 7.45 (dd, J=7.9, 4.8 Hz, 1H), 7.19 (s, 1H), 6.45 (d, J=1.9 Hz, 1H), 5.20 (s, 2H), 4.63-4.48 (m, 2H), 4.48-4.36 (m, 2H), 3.75 (dd, J=5.4, 3.9 Hz, 2H), 3.45 (s, 3H), 3.01-2.69 (m, 2H).

2-methyl-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 210). ¹H NMR (400 MHz, CDCl₃) δ 10.23 (s, 1H), 8.64 (dd, J=4.7, 1.6 Hz, 1H), 8.16 (dd, J=7.9, 1.5 Hz, 1H), 7.61 (d, J=1.9 Hz, 1H), 7.38 (dd, J=7.9, 4.8 Hz, 1H), 7.21 (d, J=8.6 Hz, 1H), 7.10 (d, J=8.6 Hz, 1H), 6.47 (d, J=1.9 Hz, 1H), 5.19 (q, J=8.6 Hz, 2H), 5.12 (d, J=6.1 Hz, 2H), 2.51 (s, 3H).

2-methyl-5-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 211). ¹H NMR (400 MHz, CDCl₃) δ 10.31 (s, 1H), 8.75 (dd, J=4.7, 1.7 Hz, 1H), 8.27 (dd, J=7.9, 1.6 Hz, 1H), 7.62 (d, J=1.9 Hz, 1H), 7.49 (dd, J=7.9, 4.8 Hz, 1H), 7.33 (d, J=8.6 Hz, 1H), 7.24 (d, J=8.6 Hz, 1H), 6.46 (d, J=1.9 Hz, 1H), 5.18 (s, 2H), 4.61-4.44 (m, 2H), 2.96-2.75 (m, 2H), 2.62 (s, 3H).

3-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 212). ¹H NMR (400 MHz, CDCl₃) δ 10.26 (s, 1H), 8.65 (dd, J=4.7, 1.5 Hz, 1H), 8.38 (dd, J=4.4, 1.0 Hz, 1H), 8.19 (dd, J=7.9, 1.0 Hz, 1H), 7.61 (d, J=1.9 Hz, 1H), 7.43-7.33 (m, 2H), 7.21 (d, J=8.6 Hz, 1H), 6.48 (d, J=1.9 Hz, 1H), 5.19 (q, J=8.6 Hz, 2H), 5.15 (s, 2H).

3-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 213). ¹H NMR (400 MHz, CDCl₃) δ 10.24 (s, 1H), 8.66 (dd, J=4.7, 1.6 Hz, 1H), 8.39 (dd, J=4.5, 1.1 Hz, 1H), 8.21 (dd, J=7.9, 1.6 Hz, 1H), 7.53 (d. J=1.9 Hz, 1H), 7.44-7.37 (m, 2H), 7.26 (d, J=8.5 Hz, 1H), 6.37 (d, J=1.9 Hz, 1H), 5.13 (s, 2H), 4.49-4.40 (m, 2H), 2.87-2.64 (m, 2H).

3-chloro-5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 214). ¹H NMR (400 MHz, CDCl₃) δ 10.51 (s, 1H), 8.77 (dd, J=4.7, 1.6 Hz, 1H), 8.41 (s, 1H), 8.28 (s, 1H), 8.13 (dd, J=7.9, 1.5 Hz, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.47 (dd, J=7.9, 4.8 Hz, 1H), 6.37 (d, J=1.8 Hz, 1H), 5.23 (s, 2H), 4.66 (sep, J=6.6 Hz, 1H), 1.49 (d, J=6.6 Hz, 6H).

3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-5-methylisonicotinaldehyde (Compound 215). ¹H NMR (400 MHz, CDCl₃) δ 10.58 (s, 1H), 8.69 (dd, J=4.7, 1.5 Hz, 1H), 8.18 (d, J=3.7 Hz, 2H), 7.92 (dd, J=7.9, 1.2 Hz, 1H), 7.53 (d, J=1.8 Hz, 1H), 7.36 (dd, J=7.9, 4.8 Hz, 1H), 7.19 (s, 1H), 6.29 (d, J=1.8 Hz, 1H), 5.14 (s, 2H), 4.59 (sep, J=6.6 Hz, 1H), 1.41 (d, J=6.6 Hz, 6H).

3-chloro-5-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 216). ¹H NMR (400 MHz, CDCl₃) δ 10.43 (s, 14), 8.67 (dd, J=4.7, 1.5 Hz, 1H), 8.35 (s, 1H), 8.26 (s, 1H), 8.06 (dd, J=7.9, 1.3 Hz, 1H), 7.61 (d, J=1.9 Hz, 1H), 7.40 (dd, J=7.9, 4.8 Hz, 1H), 6.47 (d, J=1.9 Hz, 1H), 5.21-5.10 (m, 4H).

3-methyl-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 217). ¹H NMR (400 MHz, CDCl₃) δ 10.68 (s, 1H), 8.77 (dd, J=4.7, 1.3 Hz, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 8.04 (d, J=7.9 Hz, 1H), 7.69 (d, J=1.9 Hz, 1H), 7.47 (dd, J=7.9, 4.8 Hz, 1H), 6.55 (d, J=1.9 Hz, 1H), 5.34-5.22 (m, 4H), 2.57 (s, 3H).

In Vitro Testing

Example 95 Modulation of Hemoglobin Oxygen Affinity by Heteroaryl Aldehydes—Assay Procedure

Oxygen equilibrium curves (OEC) in purified Hemoglobin S (HbS) were measured by the change in p50, the partial pressure of oxygen at which the heme binding sites in the HbS sample are 50% saturated with oxygen. HbS was purified by a modified procedure (Antonini and Brunori, 1971; Heomoglobin and Myoglobin in their Reactions with Ligands; North Holland Publishing Company; Amsterdam, London) from blood obtained from homozygous sickle cell patients though the Hemoglobinopathy Center at Children's Hospital Oakland Research Institute (CHORI) with Institutional Review Board approval. Oxygen equilibrium curves were carried out with a HEMOX analyzer, (TCS Scientific, New Hope, Pa.). Five hundred μL of 250 μM purified HbS were diluted into 4.5 mL of HEMOX buffer (30 mM TES, 130 mM NaCl, 5 mM KCl, pH=7.4) resulting in a final hemoglobin concentration of 25 μM. The compounds were added at the final desired concentrations. The mixture was incubated for 45 min at 37° C. and then transferred to the Hemox sample chamber. The samples were saturated with oxygen by flushing with compressed air for 10 minutes. The samples were then flushed with pure nitrogen and the absorbance of deoxy-Hb was recorded as a function of the solution pO₂. The oxygen equilibrium data was then fit to the Hill Model to obtain values for p50. The deoxygenation curves for both HbS alone (control) and HbS in the presence of compound were collected with the TCS software. The p50 for purified Hbs was typically 13.8±1.6. Delta p50 values were obtained from the p50 value for control minus the p50 value for HbS treated with compound divided by the p50 value for the control. A positive delta p50 value corresponds to a left shifted curve and a lower p50 value relative to control, indicating that the compound acts to modulate HbS to increase its affinity for oxygen.

Example 96 Modulation of Hemoglobin Oxygen Affinity by Heteroaryl Aldehydes—Assay Results

The compounds of Table 1 that were where tested in the assay above were all found to have positive delta p50 values. Delta p50% is calculated from [[p50(HbS) −p50(HbS treated with compound)]/p50(HbS)]×100. Table 2 below lists the delta p50% values where + indicates a delta p50% of between 0 and 29, ++ indicates a delta p50% of between 30 and 50, and +++ indicates a delta p50% of 50 or greater. Unless noted otherwise, the compounds in Table 2 were tested at 30 μM.

TABLE 2 delta p50% Compound delta p50 1 + 2 ++ (100 μM) 3 + 4 + 5 ++ 6 + 7 + 12 + (100 μM) 38 + 39 + 40 + (100 μM) 41 + 42 + 43 ++ 44 +++ 45 +++ 46 ++ 47 + 48 ++ (100 μM) 49 ++ 50 + 51 + 52 + (100 μM) 53 ++ 54 ++ (100 μM) 55 + (100 μM) 56 + (100 μM) 57 ++ (100 μM) 58 ++ 59 + 61 + 62 + 63 +++ 64 + 65 ++ 66 ++ 68 + 69 + 70 + 71 + 72 + 73 + 74 ++ 75 + 76 + 77 + 78 + 79 ++ 80 ++ 81 + 82 + 83 + 84 ++ 85 + 86 ++ 87 + 88 + 89 + 90 + 91 ++ 92 ++ 93 ++ 94 + 95 + 96 + 97 + 98 + 99 + 100 + 101 + 102 + 103 ++ 104 + 105 + 106 ++ 107 + 108 ++ 109 + 110 + 111 + 112 + 113 + 114 + 115 + 116 + 117 + 118 + 119 ++ 120 ++ 121 + 122 + 123 + 124 + 125 + 126 + 127 + 128 + 129 ++ 130 ++ 131 ++ 132 +++ 133 ++ 134 ++ 135 + 136 + 137 + 138 + 139 + 140 ++ 141 + 142 + 143 ++ 149 +++ 150 +++ 158 ++ 159 +++ 160 +++ 161 ++ 162 +++ 163 +++ 164 ++ 165 ++ 169 ++ 172 ++ 173 +++ 174 +++ 175 +++ 176 +++ 177 +++ 178 ++ 179 ++ 180 +++ 181 +++ 183 +++ 184 ++ 186 +++ 187 ++ 188 +++ 189 ++ 190 +++ 191 +++ 193 ++ 194 ++ 195 +++ 196 +++ 197 ++ 198 +++ 199 +++ 200 ++ 201 ++ 202 +++ 203 +++

Example 97 Polymerization Assay

Polymerization assays are carried out in vitro using purified HBS exchanged into 1.8 M potassium phosphate buffer at pH 7.4. Using a slightly modified protocol (Antonini and Brunori, 1971), HbS is purified by the CRO VIRUSYS, from blood obtained from homozygous sickle cell patients through the Hemoglobinopathy Center at Children's Hospital Oakland Research Institute (CHORI) with Institutional Review Board approval. Compounds are prepared in 100% DMSO and a desired amount is added to 50 μM of purified HBS at a final DMSO concentration of 0.3%. Final potassium phosphate concentration is adjusted to 1.8 M using a combination of 2.5 M potassium phosphate stock solution and water at pH 7.4. The reaction mixture is incubated for an hour at 37° C. and then transferred into a 24-well plate for deoxygenation in a glove box containing 99.5% nitrogen and 0.5% oxygen. The 24-well plate is not covered and incubated at 4° C. on a plate cooler inside the glove box for one and a half hours. Fifty μL of the reaction mixture is transferred into a 96-well plate and the absorbance at 700 nm is measured every minute for one hour at 37° C. in a plate reader located inside the glove box. A plot of the absorbance against time is fitted using a Boltzman sigmoidal fit and the delay time (from zero to time at half Vmax) is measured. To compare and rank compounds, delay times are expressed as percent delay (% DT), which is defined as the difference in delay times for HBS/compound and HBS alone multiplied by 100 and divided by the delay time for HBS alone.

Compounds listed below have been tested in the polymerization assay. Activity ranges are defined by the number of dagger (†) symbols indicated. † denotes activity ≥40% but ≤80%; †† denotes activity >80% but ≤120%; ††† denotes activity >120% but ≤140%; †††† denotes activity >160%.

TABLE 3 % delta Delay Compound % delta Delay 5 † 108 130 † 132 91 149 † 150 ††† 158 † 179 159 †† 160 †† 161 162 †† 173 † 174 †† 195 ††† 197 † 198 † 175 †† 162 †† 203 †† 163 †† 181 ††† 206 ††† 178 † 180 † 199 ††† 176 † 177 † 202 ††† 187 †† 164 ††† 165 ††† 169 ††† 186 †††† 188 ††† 189 ††† 190 †††

Example 98 R/T Assay

A relaxed-to-tense transition assay (“R/T assay”) was used to determine the ability of substituted benzaldehyde compounds to maintain the high-oxygen affinity relaxed (R) state of hemoglobin under deoxygenated conditions. This ability can be expressed as a “delta R” value (i.e., the change in the time-period of the R state after hemoglobin is treated with a compound, as compared to the period without treatment with the compound). Delta R is the % R to remaining after the compounds treatment compared with no treatment (e.g. if R % without treatment is 8% while with treatment with a target compound is 48% R at 30 μM, then % R is 40% for that compound.

A mixture of HbS/A was purified from blood obtained from homozygous sickle cell patients though the Hemoglobinopathy Center at Children's Hospital Oakland Research Institute (CHORI) with Institutional Review Board approval. HbS/A (at a final concentration of 3 μM) was incubated for 1 hr at 37° C. in presence or absence of compounds in 50 μM potassium phosphate buffer, pH=7.4 and 30 μM 2, 3 diphosphoglycerate (DPG) in 96 well plates in a final volume of 160 μl. Compounds were added at different concentrations (3 μM to 100 μM final concentrations). Plates were covered with a Mylar film. After incubation was completed the Mylar cover was removed and the plates were placed in a Spectrostar Nano plate reader previously heated at 37° C. Five minutes later, N₂ (flow rate=20 L/min) was flowed through the spectrophotometer. Spectroscopic measurements (300 nm to 700 nm) were taken every 5 min for 2 hours. Data analysis was performed by using linear regression from the data retrieved for all wavelengths.

Table 4 below lists the delta R values where + indicates a delta R of between 0 and 30, ++ indicates a delta R of between 30 and 50, and +++ indicates a delta R of 50 or greater. Unless noted otherwise, the compounds in Table 2 were tested at 30 μM.

TABLE 4 delta R Compound delta R  5 ++  43 + (9 μM)  45 ++ (9 μM)  46 + (9 μM)  53 + (9 μM)  58 + (9 μM)  63 ++ (9 μM) 193 + (9 μM)  65 + (9 μM)  66 ++ (9 μM)  79 ++ (9 μM)  80 +++ (9 μM)  84 ++ (9 μM)  86 + (9 μM)  91 +++ (9 μM)  92 + (9 μM)  93 + (9 μM) 103 ++ (9 μM) 108 +++ (9 μM) 119 ++ (9 μM) 120 ++ (9 μM) 129 ++ (9 μM) 130 + (9 μM) 131 + (9 μM) 132 ++ 133 ++ (9 μM) 134 + (9 μM) 140 + (9 μM) 143 + (9 μM) 149 + (9 μM) 150 +++ 194 + (9 μM) 158 + (9 μM) 179 + (9 μM) 159 ++ 160 + 161 + (9 μM)  172) + (9 μM) 191 + (9 μM) 173 +++ 195 +++ 174 ++ 196 ++ 197 + (9 μM) 198 ++ 175 ++ 162 +++ 203 + (9 μM) 163 ++ 181 + (9 μM) 206 + (9 μM) 178 + (9 μM) 180 ++ 199 + (9 μM) 176 + (9 μM) 177 + (3 μM) 183 ++ 184 ++ 200 + (9 μM) 201 + (9 μM) 202 + (9 μM) 187 +++ (9 μM) 164 ++ (9 μM) 165 + (9 μM) 169 ++ (9 μM) 186 +++

Example 99 Whole Blood Assay

Oxygen Equilibrium Curves (OEC) of whole blood before and after treatment with different concentrations of substituted benzaldehyde compounds were performed as follows using a HEMOX analyzer (TCS Scientific, New Hope, Pa.). Blood samples from homozygous sickle cell patients were obtained though the Hemoglobinopathy Center at Children's Hospital Oakland Research Institute (CHORI) with Institutional Review Board approval. The hematocrit was adjusted to 20% using autologous plasma and the blood samples were incubated for 1 hour at 37° C. in absence or presence of compounds. 100 μl of these samples were added to 5 mL of Hemox buffer (30 mM TES, 130 mM NaCl, 5 mM KCl, pH=7.4) at 37° C. and then transferred to the Hemox sample chamber. The samples were saturated with oxygen by flushing with compressed air for 10 minutes. The samples were then flushed with pure nitrogen and the respective absorbances of oxy- and deoxy-Hb are recorded as a function of the solution pO2. The oxygen equilibrium data were then fitted to the Hill Model to obtain values for p50. The deoxygenation curves for both whole blood alone (control) and whole blood in the presence of the compound were collected with the TCS software.

Table 5 below lists the delta p50% values where + indicates a delta p50% of between 0 and 29, ++ indicates a delta p50% of between 30 and 50, and +++ indicates a delta p50% of 50 or greater. Unless noted otherwise, the compounds in Table 2 were tested at 1000 μM. A positive delta p50 value corresponds to a left shifted curve and a lower p50 value relative to control, indicating that the compound acts to modulate HbS to increase its affinity for oxygen.

TABLE 5 delta p50% Values for Whole Blood Assay Compound delta p50% 5 + 44 + 58 + 65 + 74 ++ 79 + 80 + 92 + 93 + 103 + 106 + 108 + 120 + 129 ++ 130 ++ 131 + 132 ++ 133 + 140 + 143 + 149 +++ 150 +++ 194 + 158 + 179 ++ 159 +++ 160 +++ 191 +++ 173 +++ 174 +++ 195 +++ 196 ++ 197 +++ 198 +++ 175 +++ 162 +++ 209 + 163 +++ 181 +++ 206 +++ 178 ++ 180 +++ 199 + 176 +++ 177 +++ 183 +++ 184 +++ 200 +++ 201 + 202 + 187 + 164 ++ 165 + 169 ++ 186 +++ 188 +++ 189 +++ 190 +++

All patents, patent applications, publications and presentations referred to herein are incorporated by reference in their entirety. Any conflict between any reference cited herein and the teaching of this specification is to be resolved in favor of the latter. Similarly, any conflict between an art-recognized definition of a word or phrase and a definition of the word or phrase as provided in this specification is to be resolved in favor of the latter. 

What is claimed is:
 1. A compound of formula:

or a salt thereof.
 2. The compound of claim 1, wherein the compound is:


3. A compound of formula:

or a salt thereof.
 4. The compound of claim 3, wherein the compound is:


5. The compound of claim 3, wherein the salt is a hydrochloric acid salt. 